Field of the Invention
[0001] The present invention is directed to a process for modifying the solid state of compounds
and to compounds modified with the process of the invention. In particular, the invention
is directed a process for the preparation of non-crystalline and crystalline forms
of chemical compounds, such as pharmaceutical and nutrient compounds, and to non-crystalline
and crystalline compounds prepared with the method of the invention.
Background
[0002] Many pharmaceutical solids can exist in different physical forms. Polymorphism is
often defined as the ability of a compound to exist in at least two crystalline phases,
where each crystalline phase has a different arrangement and/or conformation of molecules
in a crystalline lattice. Non-crystalline solids consist of disordered arrangements
of molecules, and do not possess a distinguishable crystal lattice.
[0003] The non-crystalline and different polymorphic forms of a pharmaceutical solid differ
in internal solid state structure, and, thus, typically have different chemical and
physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial,
solubility, reactivity, and mechanical properties. Those properties can have a direct
impact on the quality and/or performance of a drug product, including its stability,
dissolution rate, and bioavailability.
[0004] For example, until recently, the original crystalline form of aspirin, known as Form
I, was the only known crystalline form of aspirin and the only form of aspirin that
is stable at room temperature. However, as reported in
Chemical & Engineering News, November 21, 2005, Zaworotko et al., J. Am. Chem. Soc.,
2005, 127, 16802, reported the synthesis of a second polymorphic form of aspirin. Aspirin Form II
is kinetically stable at 100 K (-173°C), but converts back to Form I at ambient conditions.
[0005] Amorphous glass aspirin has also been formed. However, except, possibly, for some
microscopic residues, amorphous aspirin has been produced only at very low temperatures.
Above the glass transition temperature of about 243 Kelvin (-30°C), amorphous aspirin
converts rapidly to the crystalline Form I. Thus, all prior art forms of aspirin convert
to Form I at room temperature. As a result of the low temperature required to create
and maintain the amorphous form, there has been essentially no practical application
of the amorphous solid state form.
[0006] Johari et al., Physical Chemistry Chemical Physics, 2000, 2, 5479-5484, also report the vitrification of aspirin by melting and cooling and by ball-milling
at ambient temperature to form a vitreous or supercooled viscous liquid aspirin that
is stable against crystallization for several days at 298K. The viscous liquid was
found to flow slowly when tilted in a container, but did not crystallize for four
to five days at 298K. The vitreous aspirin samples did ultimately undergo complete
crystallization, which was accelerated when the samples were kept at about 340K.
[0007] Johari et al. report that the vitreous state has a higher energy state than the crystal
state with a lower frequency of its phonon modes and a greater anharmonicity that
make absorption and assimilation directly from the solid state more effective and
efficient. In its bulk form, the vitreous aspirin is reported to dissolve more slowly
than the same mass of finely powdered crystals of aspirin. As is well known in the
art, a bulk sample of a substance has a significantly smaller surface area than finely
powdered crystals. That makes the dissolution of the bulk form much more difficult,
accounting for the slower dissolution rate of the bulk vitreous aspirin reported by
Johari et al.
[0008] The most stable form of a drug substance is often used in a formulation, as it has
the lowest potential for conversion from one form to another. However, a different
form that is sufficiently stable under the predicted storage conditions can be chosen
to enhance the bioavailability of the drug product. The other form may be a metastable
polymorph, i.e., a polymorphic form that is less stable than the most stable form,
but typically does not convert to a different form during normal storage, or a non-crystalline
form. A non-crystalline form lacks the regular molecular organization of a crystalline
form, and does not need to lose crystal structure during dissolution in gastric juices.
Therefore, non-crystalline forms often dissolve more quickly, and have a greater bioavailability
than crystalline forms.
[0009] Although a non-crystalline form may be desirable for a pharmaceutical composition,
the preparation of non-crystalline forms on an industrial scale is often problematic.
Processes for the preparation of non-crystalline forms of pharmaceutical compositions
include solidification of melt, reduction of particle size, spray-drying, lyophilization
(also known as freeze-drying), removal of a solvent from crystalline structure, precipitation
of acids and bases by a change in pH, and other such techniques.
[0010] Such processes are often unsuitable or impractical for production on an industrial
scale. For example, to obtain a non-crystalline active pharmaceutical ingredient by
solidification of melt, the active pharmaceutical ingredient has to be heated beyond
its melting point, requiring the expenditure of a significant amount of energy, particularly
when the active pharmaceutical ingredient has a high specific heat and/or heat of
fusion. In addition, the melting the pharmaceutical composition may chemically alter
the active pharmaceutical ingredient. Some materials also decompose before melting,
and, thus, solidification of melt cannot be used.
[0011] Lyophilization is quite expensive on a large scale, and generally has limited capacity.
Where the solvent is organic, lyophilization often presents a disposal and/or fire
hazard.
[0012] Spray-drying requires dispersing a liquid solution in a volume of a heated gas sufficient
to evaporate the solvent, leaving particulates of the solute. The heated gas is typically
hot air or nitrogen. Spray drying, is typically limited to aqueous solutions unless
special expensive safety measures are taken. In addition, contact of the pharmaceutical
composition with the heated gas can result in degradation of the composition.
[0013] The form of a solid chemical compound, whether non-crystalline or crystalline, affects
many of the properties of the compound that are important to the formulation of a
pharmaceutical composition. The flowability of a milled solid is particularly important
in the preparation of a pharmaceutical product, as flowability affects the ease with
which a pharmaceutical composition is handled during processing. When a powdered compound
does not flow freely, it may be necessary to use one or more glidants in a tablet
or capsule formulation. Glidants used in pharmaceutical compositions include colloidal
silicon dioxide, talc, starch, or tribasic calcium phosphate.
[0014] Another important property of a pharmaceutical compound that may depend on crystallinity
is its dissolution rate in an aqueous fluid. The rate of dissolution of an active
ingredient in a patient's stomach fluid can have therapeutic consequences, as the
dissolution rate imposes an upper limit on the rate at which an orally-administered
active ingredient can reach the bloodstream of a patient. The solid state form of
a compound may also affect its behavior on compaction and its storage stability.
[0015] The discovery of new non-crystalline and crystalline forms of a pharmaceutically
useful compound provides a new opportunity to improve the performance characteristics
of a pharmaceutical product. It enlarges the repertoire of materials that a formulation
scientist has available for designing, for example, a pharmaceutical dosage form of
a drug with a targeted release profile or other desired characteristic.
Summary of the Invention
[0016] The invention is directed to non-crystalline, co-amorphous pharmaceutical compositions,
and process for the preparation of the compositions of the invention. The non-crystalline
co-amorphous pharmaceutical composition comprises a solid non-crystalline, co-amorphous
blend of at least two pharmaceutical compounds. The pharmaceutical compounds are selected
from the group consisting of aspirin, ezetimibe, simvastatin, atorvastatin free acid,
atorvastatin calcium, and rosuvastatin calcium. Most preferably, the co-amorphous
pharmaceutical composition is selected from the group consisting of ezetimibe/simvastatin,
ezetimibe/atorvastatin calcium, ezetimibe/atorvastatin free acid, ezetimibe/rosuvastatin
calcium, ezetirnibe/simvastatin/aspirin, ezetimibe/atorvastatin calcium/aspirin, ezetimibe/atorvastatin
free acid/aspirin, and ezetimibe/rosuvastatin calcium/aspirin, as well as co-amorphous
compositions comprising at least one statin and aspirin. Co-amorphous statin/aspirin
compositions include, but are not limited to, atorvastatin free acid/aspirin, atorvastatin
calcium/aspirin, simvastatin/aspirin, and rosuvastatin calcium/aspirin. Preferably,
the co-amorphous pharmaceutical composition is homogeneous.
[0017] The invention provides a process for preparing the co-amorphous pharmaceutical composition
defined above. The process comprises applying laser radiation from at least two different
lasers to a solution of the at least two pharmaceutical compounds in a solvent, and
evaporating the solvent. Preferably, the laser radiation is pulsed, having pulses
with an effective average pulse length of no more than about 10
-9 seconds, and the pulses of laser radiation from each laser have a different wavelength.
The at least two pharmaceutical compounds are selected from the group consisting of
aspirin, ezetimibe, simvastatin, atorvastatin free acid, atorvastatin calcium, rosuvastatin
calcium, and mixtures thereof.
[0018] Preferably, the laser radiation used in the process comprises laser emissions modified
with a Strachan Device, where the Strachan Device comprises a first diffraction grating
and a second diffraction grating and a refractive element positioned between the first
and second diffraction gratings. Preferably, the lasers used with the Strachan Device
are diode lasers.
[0019] The process of the invention, preferably comprises obtaining a solution of the at
least one organic compound in a solvent, placing the solution of the at least one
organic compound in a covered container, applying the laser radiation to the solution,
and evaporating at least a portion of the solvent while applying the laser radiation,
thereby forming the non-crystalline composition.
[0020] More preferably, the process for preparing a non-crystalline composition of the invention
comprises passing laser radiation through a Strachan Device, the Strachan Device comprising
a first diffraction grating and a second diffraction grating and a refractive element
positioned between the first and second diffraction gratings, canceling a portion
of the laser radiation by destructive interference, and producing pulses of laser
radiation by constructive interference. The laser radiation passed through the Strachan
Device is applied to a solution comprising at least one pharmaceutical composition
in a solvent, and the solvent is evaporated.
Brief Description of the Drawings
[0021]
Figure 1 illustrates the Powder X-ray Diffraction (PXRD) pattern of a crystalline
aspirin sample;
Figure 2 illustrates a Fourier Transform Infrared (FTIR) spectrum of the crystalline
aspirin sample;
Figure 3 illustrates the PXRD pattern of a sample of aspirin treated with the process
of the invention;
Figure 4 illustrates the FTIR spectrum of the non-crystalline aspirin;
Figure 5 illustrates the PXRD pattern of a sample of crystalline aspirin formed in
the process of the invention, with the exception that laser radiation was not applied;
Figure 6 illustrates an FTIR spectrum of the crystalline aspirin sample of Figure
5;
Figure 7 illustrates the PXRD pattern of a sample of crystalline simvastatin;
Figure 8 illustrates the FTIR spectrum of the crystalline simvastatin;
Figure 9 illustrates the PXRD pattern of a sample of simvastatin treated with the
process of the invention;
Figure 10 illustrates the FTIR spectrum of the simvastatin treated with the process
of the invention;
Figure 11 illustrates the PXRD pattern of a sample of crystalline ezetimibe;
Figure 12 illustrates the FTIR spectrum of the crystalline ezetimibe, and the FTIR
spectrum of a sample of ezetimibe treated with the process of the invention;
Figure 13 illustrates the PXRD pattern of the ezetimibe treated with the process of
the invention;
Figure 14 illustrates a comparison of the PXRD pattern of a reference sample of crystalline
ezetimibe and a sample of crystalline ezetimibe produced with the process of the invention,
where the PXRD pattern of the crystalline ezetimibe produced with the process of the
invention is different from that of the control crystalline ezetimibe;
Figure 15 illustrates the PXRD pattern of a sample of crystalline atorvastatin free
acid;
Figure 16 illustrates the PXRD pattern of a sample of atorvastatin free acid treated
with the process of the invention;
Figure 17 illustrates the FTIR spectrum of a sample of crystalline atorvastatin free
acid;
Figure 18 illustrates the FTIR spectrum a sample of atorvastatin free acid treated
with the process of the invention;
Figure 19 illustrates the PXRD pattern of a sample of crystalline atorvastatin calcium;
Figure 20 illustrates the PXRD pattern of a sample of atorvastatin calcium treated
with the process of the invention;
Figure 21 illustrates the FTIR spectrum of a sample of crystalline atorvastatin calcium;
Figure 22 illustrates the FTIR spectrum of a sample of atorvastatin calcium treated
with the process of the invention;
Figure 23 illustrates the PXRD patterns comparing amorphous atorvastatin calcium Form
23 to Form 27;
Figure 24 illustrates the small angle X-ray scattering (SAXS) patterns comparing amorphous
atorvastatin calcium Form 23 to Form 27;
Figure 25 illustrates the PXRD pattern of a reference sample of rosuvastatin calcium;
Figure 26 illustrates the PXRD pattern of rosuvastatin calcium treated with the process
of the invention;
Figure 27 illustrates the FTIR spectrum of the reference sample of rosuvastatin calcium;
Figure 28 illustrates the FTIR spectrum of rosuvastatin treated with the process of
the invention;
Figure 29 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
simvastatin in a 1:1 ratio by weight;
Figure 30 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
simvastatin in a 10:20 ratio by weight;
Figure 31 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
simvastatin in a 10:40 ratio by weight;
Figure 32 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
simvastatin in a 10:80 ratio by weight;
Figure 33 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
simvastatin in a 1:1 ratio by weight with the order of the sequence of laser treatments
reversed;
Figure 34 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
simvastatin in a 10:20 ratio by weight with the order of the sequence of laser treatments
reversed;
Figure 35 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
simvastatin in a 10:40 ratio by weight with the order of the sequence of laser treatments
reversed;
Figure 36 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
simvastatin in a 10:80 ratio by weight with the order of the sequence of laser treatments
reversed;
Figure 37 illustrates a comparison of the FTIR spectrum of a laser treated sample
of ezetimibe and simvastatin in a 1:1 ratio by weight to the FTIR spectrum of the
reference sample;
Figure 38 illustrates a comparison of the FTIR spectrum of a laser treated sample
of ezetimibe and simvastatin in a 10:20 ratio by weight to the FTIR spectrum of the
reference sample;
Figure 39 illustrates a comparison of the FTIR spectrum of a laser treated sample
of ezetimibe and simvastatin in a 10:40 ratio by weight to the FTIR spectrum of the
reference sample;
Figure 40 illustrates a comparison of the FTIR spectrum of a laser treated sample
of ezetimibe and simvastatin in a 10:80 ratio by weight to the FTIR spectrum of the
reference sample;
Figure 41 illustrates a comparison of the FTIR spectrum of laser a treated sample
of ezetimibe and simvastatin in a 1:1 ratio by weight with the sequence of laser treatment
reversed to the FTIR spectrum of the reference sample;
Figure 42 illustrates a comparison of the FTIR spectrum of a laser treated sample
of ezetimibe and simvastatin in a 10:20 ratio by weight with the sequence of laser
treatment reversed to the FTIR spectrum of the reference sample;
Figure 43 illustrates a comparison of the FTIR spectrum of a laser treated sample
of ezetimibe and simvastatin in a 10:40 ratio by weight with the sequence of laser
treatment reversed to the FTIR spectrum of the reference sample;
Figure 44 illustrates a comparison of the FTIR spectrum of a laser treated sample
of ezetimibe and simvastatin in a 10:80 ratio by weight with the sequence of laser
treatment reversed to the FTIR spectrum of the reference sample;
Figure 45 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
atorvastatin calcium in a 1:1 ratio by weight;
Figure 46 illustrates the FTIR spectrum of a laser treated sample of ezetimibe and
atorvastatin calcium in a 1:1 ratio by weight;
Figure 47 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
atorvastatin free acid in a 1:1 ratio by weight;
Figure 48 illustrates the FTIR spectrum of a laser treated sample of ezetimibe and
atorvastatin free acid in a 1:1 ratio by weight;
Figure 49 illustrates the PXRD pattern of a laser treated sample of ezetimibe and
rosuvastatin calcium in a 1:1 ratio by weight;
Figure 50 illustrates the FTIR spectrum of a laser treated sample of ezetimibe and
rosuvastatin calcium in a 1:1 ratio by weight;
Figure 51 illustrates the PXRD pattern of a laser treated sample of ezetimibe, simvastatin,
and aspirin in a 2:2:1 ratio by weight;
Figure 52 illustrates FTIR spectra of a laser treated sample of ezetimibe, simvastatin,
and aspirin in a 2:2:1 ratio by weight;
Figure 53 illustrates the PXRD pattern of a laser treated sample of ezetimibe, atorvastatin
calcium, and aspirin in a 2:2:1 ratio by weight;
Figure 54 illustrates the FTIR spectrum of a laser treated sample of ezetimibe, atorvastatin
calcium, and aspirin in a 2:2:1 ratio by weight;
Figure 55 illustrates the PXRD pattern of a laser treated sample of ezetimibe, atorvastatin
free acid, and aspirin in a 2:2:1 ratio by weight;
Figure 56 illustrates the FTIR spectrum of a laser treated sample of ezetimibe, atorvastatin
free acid, and aspirin in a 2:2:1 ratio by weight;
Figure 57 illustrates the PXRD pattern of a laser treated sample of ezetimibe, rosuvastatin
calcium, and aspirin in a 2:2:1 ratio by weight;
Figure 58 illustrates the FTIR spectrum of a laser treated sample of ezetimibe, rosuvastatin
calcium, and aspirin in a 2:2:1 ratio by weight;
Figure 59 illustrates the PXRD pattern for a sample of crystalline atorvastatin free
acid formed in the process of the invention, with the exception that laser radiation
was not applied;
Figure 60 illustrates the PXRD pattern for a sample of crystalline atorvastatin calcium
formed in the process of the invention, with the exception that laser radiation was
not applied;
Figure 61 illustrates the PXRD pattern for a sample of crystalline ezetimibe/atorvastatin
calcium formed in the process of the invention, with the exception that laser radiation
was not applied;
Figure 62 illustrates the PXRD pattern for a sample of crystalline ezetimibe/atorvastatin
free acid formed in the process of the invention, with the exception that laser radiation
was not applied;
Figure 63 illustrates the PXRD pattern for a sample of crystalline ezetimibe/rosuvastatin
calcium formed in the process of the invention, with the exception that laser radiation
was not applied;
Figure 64 illustrates the PXRD pattern for a sample of crystalline ezetimibe/atorvastatin
calcium/aspirin formed in the process of the invention, with the exception that laser
radiation was not applied;
Figure 65 illustrates the PXRD pattern for a sample of crystalline ezetimibe/atorvastatin
free acid/aspirin formed in the process of the invention, with the exception that
laser radiation was not applied;
Figure 66 illustrates the PXRD pattern for a sample of crystalline ezetimibe/rosuvastatin
calcium/aspirin formed in the process of the invention, with the exception that laser
radiation was not applied;
Figure 67 illustrates the PXRD pattern for a sample of crystalline ezetimibe formed
in the process of the invention, with the exception that laser radiation was not applied;
Figure 68 illustrates the PXRD pattern for a sample of crystalline ezetimibe/simvastatin/aspirin
formed in the process of the invention, with the exception that laser radiation was
not applied;
Figure 69 illustrates the PXRD pattern of a laser treated combination of atorvastatin
calcium/aspirin in a 1:1 weight ratio;
Figure 70 illustrates the FTIR spectrum a laser treated combination of atorvastatin
calcium/aspirin in a 1:1 weight ratio;
Figure 71 illustrates the PXRD pattern of a sample of atorvastatin calcium/aspirin
in a 1:1 weight ratio formed in the process of the invention, with the exception that
laser radiation was not applied;
Figure 72 illustrates the PXRD pattern of a laser treated combination of atorvastatin
free acid/aspirin in a 1:2 weight ratio;
Figure 73 illustrates the PXRD pattern of a sample of atorvastatin free acid/aspirin
in a 1:2 weight ratio formed in the process of the invention, with the exception that
laser radiation was not applied;
Figure 74 illustrates the PXRD pattern of a laser treated combination of rosuvastatin
calcium/aspirin in a 1:1 weight ratio;
Figure 75 illustrates the PXRD pattern of a sample of rosuvastatin calcium/aspirin
in a 1:1 weight ratio formed in the process of the invention, with the exception that
laser radiation was not applied;
Figure 76 illustrates the PXRD pattern of a laser treated combination of simvastatin/aspirin
in a 2:1 weight ratio;
Figure 77 illustrates the FTIR spectrum a laser treated combination of simvastatin/aspirin
in a 2:1 weight ratio;
Figure 78 illustrates the PXRD pattern of a sample of simvastatin/aspirin in a 2:1
weight ratio formed in the process of the invention, with the exception that laser
radiation was not applied;
Figure 79 illustrates the PXRD pattern of a sample of simvastatin formed in the process
of the invention, with the exception that laser radiation was not applied;
Figure 80 illustrates the PXRD pattern of a 1:1 weight ratio sample of ezetimibe/simvastatin
formed in the process of the invention, with the exception that laser radiation was
not applied;
Figure 81 illustrates the PXRD pattern of a 1:2 weight ratio sample of ezetimibe/simvastatin
formed in the process of the invention, with the exception that laser radiation was
not applied;
Figure 82 illustrates the PXRD pattern of a 1:4 weight ratio sample of ezetimibe/simvastatin
formed in the process of the invention, with the exception that laser radiation was
not applied; and
Figure 83 illustrates the PXRD pattern of a 1:8 weight ratio sample of ezetimibe/simvastatin
formed in the process of the invention, with the exception that laser radiation was
not applied.
Detailed Description of the Invention
[0022] As used herein, with regard to the solid state of a compound, the term "non-crystalline"
refers to any solid form of the compound that, upon a powder X-ray diffraction (PXRD)
analysis, provides a PXRD pattern that is substantially free of any PXRD peaks that
are typical of a PXRD pattern of a crystalline form of the compound. Non-crystalline
compounds are typically, but need not be, amorphous.
[0023] As also used herein, the term "co-amorphous" refers to a non-crystalline blend of
two or more non-crystalline compounds, where the co-amorphous blend is produced from
a solution of the two or more compounds with the process of the invention. A co-amorphous
composition of three non-crystalline compounds may also be referred to as "tri-amorphous."
The compounds in a co-amorphous composition are typically intimately intermixed, and
are preferably substantially homogeneous. Co-amorphous compositions prepared with
the process of the invention are preferably considered solid solutions.
[0024] As discussed above, a non-crystalline form of a compound has a PXRD pattern that
is free of the characteristic peaks of a crystalline form of the compound. As a result,
the characteristic PXRD pattern of the crystalline form cannot be used to confirm
the chemical identity of the non-crystalline form. In some cases the PXRD pattern
of the non-crystalline form is known, and may be used to confirm the chemical identity.
The process of the invention is used to convert a crystalline form of a compound to
a non-crystalline or new crystalline form of the same compound. Thus, a method is
typically required to confirm that the chemical identity of the converted compound
remained unchanged. That is, a confirmation that no chemical reaction occurred during
the process of the invention is required. A Fourier Transform Infrared (FTIR) spectroscopy
analysis of a non-crystalline composition provides that confirmation.
[0025] An FTIR analysis of a non-crystalline solid compound typically results in an FTIR
pattern in which the absorption bands may be broadened slightly compared to the FTIR
pattern obtained from a crystalline form of the compound. Infrared spectra of crystalline
materials typically exhibit sharper and/or higher resolution absorption bands than
the non-crystalline form. Some shifting of bands in the infrared spectrum may also
be observed, as a result of changes in form between crystalline materials and the
non-crystalline form of the same compound. However, the changes in the FTIR spectra
between the non-crystalline and crystalline forms are sufficiently small to allow
confirmation of the identity of the non-crystalline form of the compound by comparing
the FTIR spectra of the crystalline and non-crystalline forms.
[0026] The present invention is directed to stable crystalline and non-crystalline forms
of organic compositions, particularly pharmaceutical compositions, that are stable
at room temperature and to processes for producing the stable crystalline and non-crystalline
forms with the process of the invention. The crystalline and non-crystalline forms
of pharmaceutical compositions of the invention are stable at a relative humidity
of about 30 to about 40 percent and a temperature of about 20° to 30°C for at least
about 24 hours, preferably, for at least about 30 days, more preferably, for at least
three months, and, most preferably, for at least about six months. Samples of non-crystalline
forms of the pharmaceutical compositions of the invention have remained stable and
non-crystalline at a relative humidity of about 30 to about 40 percent and a temperature
of about 20° to 30°C for at least about two years.
[0027] Non-crystalline compositions prepared with the process of the invention include non-crystalline
compositions comprising aspirin, ezetimibe, simvastatin, atorvastatin free acid, atorvastatin
calcium, rosuvastatin calcium, and co-amorphous compositions of those compounds. Non-crystalline
co-amorphous compositions of the invention prepared with the process of the invention
include, but are not limited to, ezetimibe/simvastatin, ezetimibe/atorvastatin calcium,
ezetimibe/atorvastatin free acid, ezetimibe/rosuvastatin calcium, ezetimibe/simvastatin/aspirin,
ezetimibe/atorvastatin calcium/aspirin, ezetimibe/atorvastatin free acid/aspirin,
and ezetimibe/rosuvastatin calcium/aspirin, as well as co-amorphous compositions comprising
at least one statin and aspirin. Co-amorphous statin/aspirin compositions include
atorvastatin free acid/aspirin, atorvastatin calcium/aspirin, simvastatin/aspirin,
and rosuvastatin calcium/aspirin. The weight ratio of the pharmaceutical compositions
in the treated composition is preferably adjusted to provide the desired dosage of
each pharmaceutical composition.
[0028] Without being bound by theory, it is believed that the non-crystalline form of a
compound has a higher free energy in the intermolecular lattice than any of the crystallized
forms of the compound. This imparts a higher solubility in water to the non-crystalline
form that may be about 2 to 8 times higher than that of the crystalline form, where
the non-crystalline and crystalline forms have similar particle sizes. Such an increase
in solubility can translate to faster dissolution, absorption, and clinical action,
as well as significantly higher bioavailability.
[0029] Thus, the non-crystalline pharmaceutical compositions of the invention provide a
more rapid dissolution rate than crystalline forms of the same compositions under
conditions following oral ingestion or trans-mucosal delivery, such as sublingual,
and provide higher solubility and bioavailability. Accordingly, the non-crystalline
pharmaceutical compositions of the invention, which are stable for extended periods
of time at a relative humidity of about 30 to about 40 percent and a temperature of
from about 20° to about 30°C, should have clinical and other advantages over the crystalline
forms.
[0030] It should be noted that significantly high molar ratios of aspirin to statins have
been readily achieved with the process of the invention. Without being bound by theory,
it is believed that the greater aqueous solubility of aspirin compared to that of
statins in the co-amorphous statin/aspirin compositions of the invention provide a
significantly increased relative aqueous solubility of the statin.
[0031] A crystalline form of a compound has a PXRD pattern with characteristic peaks at
particular reflection angles of the X-ray beam, measured in degrees 2θ. Typically,
the resolution of a measurement is on the order of ± 0.2° 2θ. The reflections are
the result of the regular arrangement of the molecules in the crystal. In contrast,
a partially non-crystalline sample of a compound has a PXRD pattern with substantially
blunted or reduced peaks, and a sample of a purely non-crystalline compound has a
PXRD pattern that is typically free of any characteristic peaks. The molecules are
arranged randomly in a non-crystalline compound, and, thus, the reflection peaks are
not observed in the PXRD pattern. Changes in intensity that occur over broad ranges
may be observed in some non-crystalline compounds along with baseline noise.
[0032] For example, a powder X-ray diffraction (PXRD) analysis of crystalline aspirin and
the non-crystalline aspirin prepared with the process of the invention demonstrates
the difference in the arrangement of molecules in crystalline and non-crystalline
forms. A typical PXRD pattern for commercially available crystalline aspirin is illustrated
in Figure 1. The PXRD pattern of Figure 1 has a number of peaks, characteristic of
crystalline aspirin.
[0033] In contrast, Figure 3 illustrates the PXRD pattern of non-crystalline aspirin prepared
with the process of the invention. The PXRD pattern of the non-crystalline aspirin
is in marked contrast to the highly crystalline pattern shown in Figure 1 for the
crystalline aspirin. The high intensity PXRD peaks of the crystalline aspirin are
substantially absent, indicating that, at most, only very short range ordering is
present in the non-crystalline aspirin of the invention. It is important to note that
the resolution of the PXRD pattern of Figure 1 is more than seven times greater than
the resolution of the pattern illustrated in Figure 3. Therefore, any of the peaks
observed in the PXRD pattern of the crystalline aspirin in Figure 1 that may be present
in the PXRD pattern of the non-crystalline aspirin in Figure 3 effectively have intensities
no greater than the baseline noise in Figure 1. This is clear evidence that the aspirin
analyzed by PXRD, as illustrated in Figure 3, is substantially pure non-crystalline
aspirin. Ordering of the aspirin molecules in the sample that would result in PXRD
peaks is substantially absent.
[0034] Given the strong thermodynamic tendency of some compounds, such as aspirin, to crystallize
at room temperature, very short range microcrystalline formations may be present in
a non-crystalline composition, such as the non-crystalline aspirin illustrated in
Figure 3. However, the room temperature PXRD patterns obtained for non-crystalline
compositions prepared with the process of the invention suggests that, at most, microcrystalline
structures, having very short range ordering of not more than a few molecules, may
be scattered randomly throughout the composition. Substantially the entire sample
is made up of a continuous phase of complete randomization typical of a true glass
that may contain a few, random microcrystalline structures, having very short range
ordering. The physical and chemical properties of the non-crystalline composition
prepared with the process of the invention are believed to be substantially the same
as those that would be expected of a pure glass. The arrangement of molecules is substantially
random, likely making the non-crystalline composition more soluble than the crystalline
form.
[0035] As with the disappearance of the characteristic reflection peaks of a PXRD pattern,
the Fourier Transform Infrared (FTIR) spectroscopy absorption bands are typically
broadened as the amount of the non-crystalline form of the compound increases in the
sample. This provides additional evidence of the presence of the non-crystalline form.
Infrared spectra of crystalline materials typically exhibit sharper or better resolved
absorption bands than the non-crystalline form. Some bands in an infrared spectrum
may also be shifted somewhat because of changes in form between crystalline materials
and the non-crystalline form of the same compound.
[0036] For example, the results of FTIR analyses of crystalline and non-crystalline aspirin
are illustrated in Figures 2 and 4, respectively. The aspirin samples are those analyzed
by PXRD in Figures 1 and 3. The absorption peaks of the FTIR pattern of the crystalline
aspirin, illustrated in Figure 2 are relatively well defined. In contrast, the FTIR
pattern of the non-crystalline aspirin illustrated in Figure 4 provides relatively
broad absorption bands. A comparison of the FTIR spectra of crystalline aspirin and
the non-crystalline aspirin of the invention demonstrates that the two samples are
the same chemical entity. However, the broadening of the FTIR peaks of the sample
analyzed in Figure 4 is consistent with the non-crystalline form of the compound.
[0037] The difference in the crystal structure of prior art crystalline compositions and
the non-crystalline compositions of the invention is also observed in polarized light
microscopy (PLM) photomicrographs of the crystalline and non-crystalline forms. In
polarized light microscopy, crystalline compositions produce birefringence. Birefringence
appears in anisotropic materials in which the molecules in the crystalline form are
arranged in a highly ordered pattern that is absent in the non-crystalline form. As
a result, polarized light microscopy photomicrographs of crystalline compositions
shows a high degree of birefringence that is not observed in purely non-crystalline
compositions, which lacks the ordered arrangement of molecules found in the crystalline
form.
[0038] For example, birefringence is clearly visible throughout a highly crystalline sample
in a polarized light microscopy photomicrograph of the crystalline aspirin, exhibiting
high order white interference colors. In contrast, birefringence is not observed in
polarized light microscopy photomicrographs of pure isotropic non-crystalline aspirin
particles of the invention. The absence of birefringence is evidence of the non-crystalline
compositions of the invention. As noted above, birefringence requires the ordered
arrangement of molecules that is found in the crystalline form, but is not present
in the non-crystalline form.
[0039] The non-crystalline compositions of the invention are produced by exposing a solution
of one or more chemical compounds to of laser light of different wavelengths from
at least two sources, and evaporating the solvent. The laser light may be applied
simultaneously or in alternating sequences. The compounds are preferably pharmaceutical
compositions.
[0040] Preferably, the laser radiation is pulsed at a relatively high pulse repetition rate,
having an effective pulse length no greater than the picosecond range (10
-12 to 10
-9 second), and may be in the femtosecond range (10
-15 to 10
-12 second) or the sub-femtosecond range (< 10
-15 second). One of the lasers preferably has an emission centered in the lower half
of the visible spectrum, i.e., between about 400 and about 550 nm, preferably, in
the near ultraviolet (UV) to blue range, more preferably, at a wavelength from about
400 to about 470 nm. The other laser preferably has an emission centered in the upper
half of the visible spectrum, i.e., between about 550 and about 700 nm, preferably,
in the red to near infrared (IR), more preferably at a wavelength of from about 620
to about 680 nm. Using two lasers having emissions centered at similar wavelengths,
i.e., two short wavelength lasers, two long wavelength lasers, or two lasers with
emissions centered near 550 nm, may be useful in some applications. However, good
results have been obtained with one laser having a center wavelength of from about
400 to about 470 nm and a second laser having a center wavelength of from about 620
to about 680 nm.
[0041] Without being bound by theory, it is believed that the output bandwidth of the lasers
is broadened by the short effective pulse length. This follows from the Uncertainty
Principle. As a result, the short pulses of laser light are believed to provide photons
that interact with multiple vibrational and/or electronic states in the process of
the invention to provide the non-crystalline forms. As a result, lasers having emissions
that correspond to specific absorption bands of the treated compounds are not required.
[0042] Preferably, the ultra-short laser pulses are produced by modifying the output of
the lasers to generate sparse nodes of constructive interference of electromagnetic
(EM) waves, as disclosed by
U.S. Patents Nos. 6,064,500 and
6,811,564 to Strachan, the disclosures of which are incorporated herein in their entirety by
reference. As used herein, the term "Strachan Device" refers to a device of the type
disclosed by Strachan in those patents. A Strachan Device, as defined in the '500
and '564 patents, and as used herein, comprises a first diffraction grating and a
second diffraction grating and a refractive element positioned between the first and
second diffraction gratings. When a laser beam, either continuous or pulsed, is passed
sequentially through the first diffraction grating, the refractive element, and the
second diffraction grating of a Strachan Device, at least a portion of the beam is
substantially canceled by destructive interference. The interaction of light beams
that pass through the Strachan Device results in destructive interference that substantially
cancels the beams as they exit the Strachan Device. The refractive element allows
the cancellation to occur over a small percentage of the laser source rather than
at a single critical wavelength.
[0043] Relatively sparse zones of constructive interference occur between the high and low
frequency passes of the cancellation element in selected directions from the aperture.
The sparse nodes of constructive interference occur only where the output of the Strachan
Device results in constructive interference at a distance from the device. The constructive
interference only occurs over ultra-short time periods, and, thus, results in ultra-short
pulses of light. The pulses are believed to have effective pulse lengths of no more
than about 10
-9 seconds.
[0044] With a Strachan Device, fractional changes in the wavelength of the laser or relative
amplitudes of wavelengths in the laser cause rapid translation in the location of
these nodes; as, for example, fractional changes in current in a laser diode and fluctuations
injunction temperature causing variations in the laser center frequency. As a result,
a continuous laser beam is transformed into a string of extremely short duration pulses
by the simple means of relatively small low frequency amplitude modulation. The amplitude
modulation of diode lasers at a frequency of over 1 MHz is well within the skill of
those skilled in the art. As a result, effective pulse lengths having a duration in
the picosecond range are readily attainable, and femtosecond or sub-femtosecond pulses
are attainable with a properly prepared Strachan Device and amplitude modulated diode
laser.
[0045] For example, with a continuous diode laser, the pulse repetition frequency of the
string of extremely short duration pulses is defined by the amplitude modulation frequency
of the direct laser diode drive or the acousto-optic or electro-optic modulation device.
The inherent current modulation of the direct laser drive method will result in more
fluctuation in laser center frequency reducing the period of the coincident pulses
while acousto-optic modulation provides a similar effect if the aperture of the modulated
beam is greater than the diameter of the optimal modulation aperture of the crystal,
as the outer radii will be less deeply modulated than the inner radii causing the
effective aperture in the function to alter.
[0046] In the present method of producing the non-crystalline compositions, a rapid, alternating
sequence of ultra-short laser pulses from at least two different lasers are applied
to a solution of the composition, and evaporating the solvent. As discussed above,
it is believed that the output bandwidth of the lasers is broadened by the short pulse
length. This follows from the Uncertainty Principle. As a result, the short pulses
of laser light are believed to provide photons that interact with multiple vibrational
and/or electronic states of the composition to provide the non-crystalline form. As
a result, lasers having an emission that corresponds to a specific absorption band
of the composition are not required, and, thus, the choice of lasers is not critical.
Good results have been obtained with all the pharmaceutical compositions discussed
below using a laser that emits in the blue-violet band (preferably about 400 to about
470 nm) and a laser that emits in the red to near infrared wavelength band (preferably
about 620 to about 680 nm), such as diode lasers. As the chemical structures and,
thus, the absorption spectra of the pharmaceutical compositions treated with the process
of the invention, as described herein, differ significantly, it is believed that the
process of the invention can be extended to a variety of other organic compounds.
[0047] Preferably, the preferred alternating sequence comprises sparse nodes of constructive
interference of ultra short duration in the two wavelength regions that are produced
using at least a pair of lasers and one or more Strachan Devices. Without being bound
by theory, it is believed that the alternating sequence of ultra-short laser pulses
interacts with the electronic and/or vibrational states of the molecules of the composition,
disrupting intermolecular interactions, and, thus, preventing crystal formation and/or
disrupting the crystal structure.
[0048] The room temperature stable non-crystalline compositions of the invention are preferably
produced by the alternating application of amplitude modulated sparse constructive
nodes from at least two different lasers that are passed through a Strachan Device,
and applied to a solution of the composition in a solvent. Preferably, the alternating
applications are repeated frequently.
[0049] Useful solvents are typically organic solvents in which the composition is at least
moderately soluble, that evaporate at about room temperature to about 130°C, and are
nontoxic. Preferably, the composition is dissolved in an alcohol, and, more preferably,
ethanol. Solvents are preferably anhydrous, and the most preferred solvent is anhydrous
ethanol, i.e., 100 percent or absolute ethanol.
[0050] Preferably, the laser radiation is applied to the solution until the solvent is substantially
evaporated. More preferably, the solution is heated during the application of the
laser radiation and evaporation of the solvent, but may be cooled during the evaporation
process, preferably to room temperature. Most preferably, the laser radiation is first
applied to the solution, where the solution is covered with a transparent cover that
substantially prevents evaporation of the solvent. The transparent cover is then removed,
and the application of laser radiation is preferably continued as the solvent evaporates.
[0051] Preferably, the lasers comprise a laser that emits in the blue-violet wavelength
and a laser that emits in the red-orange wavelength band. More preferably, the lasers
preferably emit in the range of about 400 to about 470 nm and in the range of about
620 to about 680 nm, respectively. More than two lasers emitting at different wavelengths
may be used with the invention. Good results have been obtained with a Strachan Device
and diode lasers that emit at 408 nm and 674 nm.
[0052] Although the process of the invention has been shown to provide non-crystalline compositions
in the presence of normal air, the process may also be performed in an inert atmosphere.
The inert atmosphere may be provided using nitrogen, helium, argon, or other inert
gas. For cost reasons, nitrogen is preferred. The use of the inert gas will eliminate
any tendency of the non-crystalline compositions to oxidize during the process.
Examples
[0053] The following non-limiting examples are merely illustrative of the preferred embodiments
of the present invention, and are not to be construed as limiting the invention, the
scope of which is defined by the appended claims.
[0054] To confirm that the non-crystalline compositions prepared with the laser treatment
of the invention were not an artifact of the experimental setup, experimental procedures
were repeated with the exception that no laser radiation was applied to the solutions.
That is samples of ezetimibe, statins, and aspirin, either individually or in combination,
were dissolved in a solvent, placed on a hotplate in a covered Petri dish, and uncovered,
allowing the solvent to evaporate, in accordance with the protocols discussed above
in the examples. A substantial amount of crystalline material was observed in each
of the comparative tests.
Example 1: Preparation of Non-crystalline Aspirin
[0055] Non-crystalline aspirin is far from thermodynamic equilibrium at room temperature,
and has always been found previously to be crystalline or to crystallize at temperatures
above the glass transitions temperature, which is well below room temperature, up
to the melt temperature. However, the repetitive application of laser radiation in
accordance with the invention, converts aspirin to a predominant non-crystalline form
that has been found to remain stable at room temperature for at least up to about
a year.
Example 1a:
[0056] A single sequence of long wavelength (red), 674 nm, followed by short wavelength
408 nm (violet) , amplitude modulated and structured laser light from a Strachan Device
was applied to a solution of aspirin in absolute ethanol. The approximately 3 cm expanded
beam from each respective laser was slowly rotated over the sample at a distance of
25 cm from the Strachan Device for 2.5 minutes for each of the wavelengths of laser
light. An analysis of the treated aspirin with plane polarized light microscopy demonstrated
the occasional production of a small fraction of tiny isotropic droplets of aspirin,
generally less than one millimeter (1 mm) in size, that were stable at room temperature
once the solvent had evaporated. Most of the droplets had a core of birefringent crystalline
material and a halo of isotropic aspirin, though a few droplets were purely isotropic.
The ability of the isotropic material to resist crystallization when abutting forming
fronts of crystallized material demonstrates the stability of the non-crystalline
aspirin of the invention produced through this method once the solvent was evaporated.
Example 1b:
[0057] The frequent, repeated sequenced application of laser radiation to produce stable
non-crystalline aspirin resulted in the production of up to about 80 to about 90 percent
or more of transparent non-crystalline aspirin. Droplets of pure glassy material of
about 2 to 3 mm or more and lakes of non-crystalline aspirin dozens of millimeters
wide have been found to be stable for up to about a year at room temperature.
[0058] As discussed above, a reference standard crystalline aspirin was analyzed by PXRD.
The characteristic pattern of reflection peaks of the reference standard crystalline
aspirin is illustrated in Figure 1. The crystalline aspirin was also analyzed using
Fourier transform infrared spectroscopy, as illustrated in Figure 2. As the PXRD pattern
of a compound in the non-crystalline state results in disappearance of characteristic
reflection peaks, FTIR spectroscopy confirms compound identification, and provides
further evidence of the non-crystalline state by showing a broadening of absorption
bands that occurs in the non-crystalline compared to the crystalline state.
[0059] The highly non-crystalline state of aspirin was produced by repeated applications
of cycles of sequences of long wavelength followed by short wavelength laser light
modulated and structured by a Strachan Device. A 10 mg sample of a crystalline aspirin
reference standard was dissolved in 450 mg of absolute ethanol by stirring at 9000
revolutions per minute (rpm) with a magnetic stirrer, while heating to 140°C for 12.5
minutes in a stoppered Erlenmeyer flask. The solution was transferred into a 60 mm
x 15 mm glass Petri dish, covered with a glass lid. The Petri dish was heated to 100°C
on a hotplate.
[0060] The aspirin solution was treated with repeated cycles of laser radiation modified
with a Strachan Device. The first cycle was the application of amplitude modulated
diode laser light from a diode laser having a central wavelength of 674 nm. The second
cycle was the application of amplitude modulated diode laser light from a diode laser
having a central wavelength of 408 nm. The sample was rotated slowly through each
approximately 3 cm expanded beam at a distance of 25 cm from the Strachan Device.
[0061] The 674 nm laser diode beam had a peak power of 4.80 mW without optics. After passing
through a Thorlabs 5x beam expander and the Strachan Device the peak power was reduced
by about 50 percent. Using the Strachan Device, the 674 nm beam was adjusted to the
80 percent phase cancellation level to achieve a power of about 0.48 mW over a 3 cm
diameter beam.
[0062] The 408 nm beam had a peak power of about 4.8 mW without added optical elements.
After passing through a Thorlabs 5x beam expander and the Strachan Device the peak
power was reduced by about 50 percent. Using the Strachan Device, the 408 nm beam
was adjusted to the 80 percent phase cancellation level to obtain a 3 cm diameter
beam of about 0.48 mW.
[0063] Both beams were electronically amplitude modulated at 6.25 Megahertz (MHz.). As discussed
above, without being bound by theory, it is believed that the output bandwidth of
the lasers is broadened by the short effective pulse length produced by the Strachan
Device, which follows from the Uncertainty Principle. This provides interaction of
the photons in the laser light with multiple electronic and/or vibrational modes of
the aspirin molecules.
[0064] The aspirin solution was treated in the covered glass Petri dish while on the hotplate
for one minute with the 674 nm configuration, then for one minute with the 408 nm
configuration as above. This was followed with another cycle of the amplitude modulated
and structured 674 nm configuration, followed by the 408 nm laser configurations for
one minute for each laser system. The third sequence of the 674 nm laser followed
by the 408 nm laser treatment was for 2 minutes with each laser system.
[0065] After this cycle the glass cover was removed from the Petri dish to permit evaporation
of the ethanol. For the duration of the laser treatments, spanning 5 more cycles,
the aspirin in ethanol solution remained on the hotplate. The next cycle of 674 nm
followed by 408 nm laser treatments was for 2 minutes with each laser system. The
next 4 cycles of 674 nm followed by 408 nm laser treatments applied 2 minutes per
cycle with the laser systems applied for one minute each per cycle. Upon completion
of the last cycle of laser treatment the sample of laser treated aspirin was removed
from the hotplate to continue the process of solvent evaporation at a room temperature
of about 18° to 20°C and a humidity of 35 percent.
[0066] At the end of the laser treatment, most of the solvent had already evaporated, resulting
in a "lake" of clear transparent non-crystalline aspirin approximately 3 cm wide.
A narrow rim of crystallization had formed around the outer margin of the lake in
a band representing approximately 30 percent of the circumferential perimeter. Despite
the formation of an active crystallization front, there was negligible extension of
this front after completion of the cycles of the sequenced laser treatments.
[0067] Within an hour of the evaporation, the system stabilized with 80 percent or more
of the mass of the sample cured to a clear non-crystalline form rather than a crystalline
form. Continued storage at a room temperature of about 18° to 22°C and about 30 to
40 percent humidity resulted in no change in appearance of the sample during a period
of over 6 months duration, with preservation of the wide expanse of transparent non-crystalline
aspirin even adjacent to the rim of crystallization. Those observations demonstrate
the stability of the non-crystalline form of aspirin produced with the method of the
invention.
[0068] After the 6 months of storage, the laser treated aspirin was studied by PXRD. This
pattern, shown in Figure 3, demonstrates this material to be highly X-ray non-crystalline,
in marked contrast to the highly crystalline pattern shown in Figure 1 for the control
crystalline aspirin. Compared to the high intensity reflection peaks seen for crystalline
aspirin, for laser treated aspirin these peaks are essentially completely eliminated,
indicating that at most only very short range ordering remains in the non-crystalline
glass form produced. No crystallization has been observed in similarly prepared samples
following an additional six months of storage. Those observations demonstrate the
stability of the non-crystalline form of aspirin produced with the method of the invention.
[0069] The X-ray non-crystalline aspirin sample was then scanned using Fourier transform
infrared (FTIR) spectroscopy, as shown in Figure 4. In comparison to the FTIR spectroscopy
of aspirin reference crystalline material shown in Figure 2, relatively broad absorption
bands are evident in the X-ray non-crystalline samples of aspirin as compared with
the more defined bands of the crystalline aspirin reference sample. Infrared spectra
of crystalline materials typically exhibit sharper or better resolved absorption bands
than the non-crystalline form because of the reduced freedom of movement of the molecules
in a crystalline lattice. Some bands in an infrared spectrum may also be shifted somewhat
because of changes in form between crystalline materials and the non-crystalline form
of the same compound. Comparing the FTIR spectra of crystalline aspirin and laser
treated aspirin, these compounds are clearly the same chemical entity. The broadening
of the spectral peaks in laser treated aspirin is an additional feature consistent
with the non-crystalline form of aspirin.
Example 1c:
[0070] Subsequent tests with the protocol of Example 1b were repeated with the order of
long and short wavelengths reversed, i.e., short wavelength followed by long wavelength
cycled sequenced laser treatment. This protocol also produced up to 90 percent yields
of room temperature stable non-crystalline glass aspirin, which remained stable at
room temperature for over 23 months. The Petri dish containing such a sample of non-crystalline
aspirin was placed on edge for a period of about six weeks. No flowing of the sample
was observed.
Comparative Example: Aspirin
[0071] The protocols of Examples 1b and 1c were repeated with the exception that there was
no application of laser radiation. The resulting material was visibly crystalline,
which was confirmed by PXRD analysis, which demonstrated that a substantial amount
of crystalline material was present. A PXRD pattern for the aspirin obtained without
the application of the laser radiation is illustrated in Figure 5. The PXRD pattern
of Figure 5 has the same peaks as that of the control sample illustrated in Figure
1. An FTIR analysis of the resulting aspirin was also performed. The resulting spectrum
is illustrated in Figure 6, and is substantially the same as that illustrated in Figure
2. Those results clearly demonstrate that the non-crystalline aspirin is not an artifact
of the experiment, but, instead, is a direct result of the application of the laser
radiation in the process of the invention.
Example 2: Preparation of Non-crystalline Simvastatin
[0072] A control sample of crystalline simvastatin was analyzed by PXRD. The characteristic
PXRD pattern of crystalline simvastatin obtained from the sample is illustrated in
Figure 7. The crystalline simvastatin was further analyzed using Fourier transform
infrared (FTIR) spectroscopy, and the FTIR absorption spectrum of the crystalline
simvastatin is illustrated in Figure 8.
[0073] To obtain non-crystalline simvastatin, a 40 mg sample of crystalline simvastatin
was dissolved in 674 mg of 100 percent (absolute) ethanol with stirring at 9000 revolutions
per minute (rpm) for 8 minutes in a stoppered Erlenmeyer flask, followed by heating
to 140°C for an additional 10 minutes at 9000 rpm. The solution was cooled to approximately
20°C, i.e., room temperature, filtered using a syringe to remove any residual crystals,
decanted into a 60 mm x 15 mm glass Petri dish, and covered with a glass lid.
[0074] The dissolved sample of laser treated simvastatin was first treated with amplitude
modulated diode laser light having a central wavelength of 674 nm for 2.5 minutes,
and then with amplitude modulated diode laser light having a central wavelength of
408 nm for 2.5 minutes, while rotating the sample slowly through each of the approximately
3 cm expanded beams at a distance of 25 cm from the output of the respective Strachan
Devices.
[0075] The 674 nm laser diode beam had a peak power of 4.80 mW without optics. After passing
through a Thorlabs 5x beam expander and the Strachan Device the peak power was reduced
by about 50 percent. Using the Strachan Device, the 674 nm beam was adjusted to the
80 percent phase cancellation level to obtain a 3 cm diameter beam of about 0.48 mW.
[0076] The 408 nm beam had a peak power of about 0.32 mW without added optical elements.
After passing through a Thorlabs 5x beam expander and the Strachan Device the peak
power was reduced by about 50 percent. Using the Strachan Device, the 408 nm beam
was adjusted to the 80 percent phase cancellation level to obtain a 3 cm diameter
beam of about 0.02 mW. Both beams were electronically amplitude modulated at 6.25
Megahertz (MHz).
[0077] The lid of the glass Petri dish was removed, and the was solution allowed to dry
through slow evaporation at a room temperature of about 19° to 20°C and 41 percent
humidity. The resultant material dried to a pure transparent glass state. The sample
of laser treated simvastatin was examined by polarizing light microscopy (PLM), and
was found to appear entirely isotropic, indicating the material was purely non-crystalline.
The laser treated simvastatin was then studied using PXRD. This pattern is illustrated
in Figure 9, and is substantially free of any of the PXRD peaks of the crystalline
simvastatin, demonstrating that the laser treated simvastatin was non-crystalline.
[0078] The non-crystalline simvastatin produced with the process of the invention was then
subjected to an FTIR analysis. The resulting FTIR spectrum is illustrated in Figure
10. In comparison to the FTIR spectrum obtained from the crystalline simvastatin illustrated
in Figure 8, the absorption bands of the FTIR spectrum of the laser treated simvastatin
are relatively broad compared with the much more defined bands of the crystalline
simvastatin reference sample.
Comparative Example: Simvastatin
[0079] The protocol of Example 2 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the simvastatin obtained without the application of
the laser radiation is illustrated in Figure 79. An FTIR analysis of the resulting
simvastatin was also performed, confirming the material was simvastatin. The results
demonstrate that the non-crystalline simvastatin is not an artifact of the experiment,
but, instead, is a direct result of the application of the laser radiation in the
process of the invention.
Example 3: Preparation of Non-crystalline Ezetimibe
[0080] Crystalline ezetimibe was subjected to analysis by light microscopy, PXRD, and FTIR
spectroscopy to serve as a reference sample for comparison to ezetimibe treated with
the process of the invention. Optical plane polarized light microscopy confirmed that
the ezetimibe reference sample was entirely birefringent, and, thus, highly crystalline.
The PXRD spectrum of the crystalline ezetimibe illustrated in Figure 11 includes the
peaks that are characteristic of the crystalline material. The characteristic FTIR
pattern of control crystalline ezetimibe is illustrated in the upper portion of Figure
12.
[0081] To obtain non-crystalline ezetimibe, 50 mg of ezetimibe was dissolved in 500 mg of
absolute ethanol, and stirred with a stir bar in a stoppered Erlenmeyer flask for
5 minutes. The stopper was removed, and the ezetimibe and absolute ethanol were then
stirred while being heated at 165°C for an additional for 6 minutes. After about 30
percent of the ethanol evaporated, the solution of ezetimibe in ethanol was decanted
into a 60 mm x 15 mm glass Petri dish. A glass cover was placed over the Petri dish,
and amplitude modulated diode laser radiation from the at 408 nm wavelength laser
was applied for 2.5 minutes, followed amplitude modulated diode laser radiation from
the 674 nm wavelength laser for 2.5 minutes.
[0082] The 408 nm beam had a peak power of about 0.48 mW without added optical elements.
After passing through a Thorlabs 5x beam expander and the Strachan Device the peak
power was reduced by about 50 percent. The 674 nm laser diode beam had a peak power
of 4.80 mW without optics. After passing through a Thorlabs 5x beam expander and the
Strachan Device the peak power was reduced by about 50 percent. Both beams were electronically
amplitude modulated at 6.25 MHz. Using the Strachan Device, both the 408 nm beam and
the 674 nm laser were adjusted to the 80 percent phase cancellation level to obtain
power levels of .05 mW and .48 mW over 3 cm diameter beams, respectively.
[0083] First, the Strachan Device modified emission of the 408 nm modulated diode laser
output was directed straight upward with the beam expanded to about 3 cm and the sample
located about 29 cm from the output of the Strachan Device for a period of about 2.5
minutes. Then, the Strachan Device modified emission of the 674 nm modulated laser
diode output was directed straight upward with the beam expanded to about 3 cm and
the sample located about 29 cm from the Strachan Device for a treatment duration of
2.5 minutes. The ezetimibe in the glass Petri dish was slowly circulated through the
beam to cover the entire surface area.
[0084] The glass cover was removed and the sample was allowed to desolvate in an open container
through slow evaporation at about 20°C and a relative humidity of 31 percent. Before
the solvent had fully evaporated, the sample developed a few small areas of apparent
crystallization that were surrounded with marker lines. As the evaporation continued,
no significant extension of the crystal fronts was observed. The fronts remained stable
for five weeks, and there was no encroachment on the predominantly isotropic glassy
material of the sample by the crystalline material, suggesting significant stability
of the non-crystalline form, even when exposed to crystallization fronts.
[0085] A light microscopy evaluation of the samples was performed using a Leica DM LP microscope
equipped with Spot Insight color camera (model 3.2.0). A 5x, 10x, 20x, or 40x objective
was used with cross polarizers and a first order red compensator in place to view
samples. Sample coatings were carefully scraped from the dishes, placed on a glass
slide, and covered with a drop of silicon oil. A cover glass was then placed over
the samples. Images were acquired at ambient temperature using Spot software (v.4.5.9
for Windows).
[0086] Analysis of the ezetimibe treated with the process of the invention demonstrated
that in excess of 90 percent of the treated ezetimibe was in the form of an isotropic
film. A PXRD analysis of the isotropic ezetimibe provided a PXRD pattern having a
very broad reflection centered at approximately 20° 2θ, confirming that the isotropic
film collected is non-crystalline. The PXRD pattern of the non-crystalline ezetimibe,
as illustrated in Figure 13, is free of the characteristic PXRD peaks of crystalline
ezetimibe.
[0087] The FTIR spectrum of the non-crystalline ezetimibe, as illustrated in the lower portion
of Figure 12, when compared to the FTIR spectrum of the crystalline ezetimibe is illustrated
in the lower portion of Figure 12 confirms that the non-crystalline material is ezetimibe.
Although the crystalline ezetimibe has an FTIR spectrum with sharper peaks than the
FTIR spectrum of the non-crystalline ezetimibe film the two FTIR spectra confirm that
the non-crystalline material is ezetimibe.
[0088] The ezetimibe treated with the process of the invention also yielded a small area
of microscopically birefringent material that remained stable for several weeks after
solvent evaporation, indicating that the isotropic, non-crystalline ezetimibe resisted
crystallization even when adjacent to an organizing crystal front, suggesting that
non-crystalline ezetimibe produced through this method, once desolvation occurs, achieves
significant stability over reversion to a crystal form.
[0089] The PXRD pattern of the birefringent ezetimibe produced with the process of the invention
proved significantly different from the crystal pattern of the reference crystalline
ezetimibe. As illustrated in Figure 8, the PXRD pattern of the microscopically birefringent
material from the laser treated ezetimibe has a PXRD pattern with peaks that are significantly
different from that of control crystalline ezetimibe. That indicates the preparation
of a different crystal form of ezetimibe.
[0090] By producing a stabilized non-crystalline pattern in the desolvating ezetimibe, a
unique crystal form different from the initial crystal form of the compound emerged
from the system. While this disclosure has focused primarily on the ability to produce
the non-crystalline state of compounds that tend to crystallize, it has been found
that the process of the invention may also be used to create conditions that favor
the generation of new polymorphic crystal forms of such compounds. In this case, a
polymorphic crystal form self organized from the conditions favoring producing the
compound in the non-crystalline state. It is believed that the process of the invention
can be applied to favor a particular solid state organization as a step or sequence
of steps before or during desolvation.
[0091] The production of small quantities of new crystal forms should be useful as seed
crystals to generate substantially larger quantities of the new form. If this new
form is less thermodynamically favored and less stable than the original form the
application of laser treatment during the process before or during desolvation until
complete may permit scaling up production of the new form to the level required for
practical use.
[0092] The new crystal form for ezetimibe shown in Figure 8 is similar though possibly not
identical to a previously reported form. Minimally this disclosure indicates a new
method through which this form can be produced. If further comparison shows they are
differentiated, then this crystal form will require testing for solubility and bioavailability
to determine if there are potential advantages to the use of this form.
Comparative Example: Ezetimibe
[0093] The protocol of Example 3 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the ezetimibe obtained without the application of
the laser radiation is illustrated in Figure 67. The PXRD pattern of Figure 67 has
the same peaks as that of the control sample illustrated in Figure 11. An FTIR analysis
of the resulting ezetimibe was also performed, confirming the material was ezetimibe.
The results demonstrate that the non-crystalline ezetimibe is not an artifact of the
experiment, but, instead, is a direct result of the application of the laser radiation
in the process of the invention.
Example 4: Preparation of Non-crystalline Atorvastatin Free Acid
[0094] A reference sample of crystalline atorvastatin free acid was analyzed with PXRD and
FTIR spectroscopy. As illustrated in Figure 15, the PXRD spectrum of crystalline atorvastatin
free acid is characterized by a PXRD having a number of specific peaks. The FTIR spectrum
of the crystalline atorvastatin free acid is illustrated in Figure 17.
[0095] A 10 mg sample of crystalline atorvastatin free acid was dissolved in 400 mg of absolute
ethanol with heating to 160°C and stirring at 9000 rpm for 11 minutes. The resulting
solution was transferred into a 60 mm x 15 mm glass Petri dish, covered with a glass
lid, and placed on a hotplate at 100°C.
[0096] First, the amplitude modulated emission of a 674 nm diode laser was applied to the
solution of atorvastatin free acid for 2.5 minutes. Then, the amplitude modulated
emission of a 408 nm diode laser was applied for 2.5 minutes, rotating the sample
slowly through the approximately 3 cm expanded beam at a distance of 25 cm from the
Strachan Device. The 674 nm laser diode beam was passed through a Thorlabs 5x beam
expander and a Strachan Device. Using the Strachan Device, the 674 nm beam was adjusted
to the 80 percent phase cancellation level to achieve a power of approximately 0.48
mW over the 3 cm diameter beam. The 408 nm beam had a peak power of 2.18 mW after
passing through a Thorlabs 5x beam expander and the Strachan Device. The output of
the 408 nm beam was also optically phase cancelled using the Strachan Device to achieve
a measured 80 percent reduction of transmitted power to 0.44 mW over the 3 cm diameter
beam. Both beams were electronically amplitude modulated at 6.25 MHz
[0097] The lid of the glass Petri dish was removed, and the solution was allowed to dry
through slow evaporation at a room temperature of about 19° to about 20°C and about
36 percent humidity. The resultant material dried to a pure transparent glass state.
The laser treated atorvastatin free acid was then studied using PXRD. The PXRD pattern
was free of the peaks characteristic of crystalline atorvastatin free acid, as illustrated
in Figure 16, and was thus, non-crystalline.
[0098] The non-crystalline atorvastatin free acid prepared with the process of the invention
was then analyzed with FTIR spectroscopy. The resulting FTIR spectrum is illustrated
in Figure 18. A comparison of the FTIR spectrum illustrated in Figure 18 with that
of the crystalline atorvastatin free acid illustrated in Figure 17, confirms that
the treated atorvastatin free acid is the same chemical entity as the crystalline
atorvastatin free acid. The FTIR spectrum of atorvastatin free acid reference exhibits
somewhat sharper peaks than the spectrum of the non-crystalline laser treated atorvastatin
free acid. However, as discussed above, broadening of the FTIR spectroscopic absorption
bands is typical of the non-crystalline compared to the crystalline form of a material
because of increased freedom of movement of molecules not confined to a crystal lattice.
Comparative Example: Atorvastatin Free Acid
[0099] The protocol of Example 4 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the atorvastatin free acid obtained without the application
of the laser radiation is illustrated in Figure 59. The PXRD pattern of Figure 59
has the same peaks as that of the control sample illustrated in Figure 15. An FTIR
analysis of the resulting atorvastatin free acid was also performed, confirming the
material was atorvastatin free acid. The results demonstrate that the non-crystalline
atorvastatin free acid is not an artifact of the experiment, but, instead, is a direct
result of the application of the laser radiation in the process of the invention.
Example 5: Preparation of Non-crystalline Atorvastatin Calcium
[0100] The initial development of atorvastatin for its cholesterol lowering benefits was
performed for atorvastatin as an amorphous solid state, designated as Form 23 or amorphous
B. When the crystalline form of atorvastatin calcium was developed, clinical trials
had already been completed for Form 23 with very favorable results. Although bioequivalence
testing showed a difference in absorption for tablets prepared with Form 23 compared
to those made with the crystalline compound, the extent of the absorption proved sufficiently
equivalent for regulatory approval of the clinical use of the crystalline form. While
atorvastatin calcium has been produced in non-crystalline forms, the present method
offers advantages both in production methods and the non-crystalline state generated
compared to the prior methods, reopening the potential for use of this more soluble
and rapidly absorbable form.
[0101] A control sample of the reference crystalline atorvastatin calcium was analyzed with
PXRD and FTIR spectroscopy. The PXRD spectrum of the crystalline atorvastatin calcium
was characterized by the PXRD peaks typical of the crystalline form, and is illustrated
in Figure 19. The FTIR spectrum of crystalline atorvastatin calcium is illustrated
in Figure 21.
[0102] A 10 mg sample of crystalline atorvastatin calcium was dissolved in 444 mg of absolute
ethanol by heating to 160°C while stirring at 9000 rpm for 11 minutes. The solution
was transferred into a 60 mm x 15 mm glass Petri dish, covered with a glass lid, and
placed on a hotplate at 100°C.
[0103] The amplitude modulated emission of a diode laser having a central wavelength of
408 nm wavelength was applied to the solution for 1 minute. Then, The amplitude modulated
emission of a diode laser having a central wavelength of 674 nm was applied for 1
minute, followed by another cycle of amplitude modulated laser light at 408 nm wavelength
for 1 minute, then with 674 nm wavelength for 1 minute, followed by a final cycle
of amplitude modulated laser light at 408 nm wavelength for 30 seconds, then with
674 nm wavelength for 30 seconds. During these cycles, the sample was rotated slowly
through each of the approximately 3 cm diameter expanded beams at a distance of 25
cm from the respective Strachan Devices. The 408 nm beam had a peak power of 2.44
mW after passing through a Thorlabs 5x beam expander and the Strachan Device. The
output of the 408 nm beam was optically phase cancelled using the Strachan Device
to achieve a measured 80 percent reduction of transmitted power to 0.48 mW over a
3 cm diameter beam. The 674 nm laser diode beam was passed through a Thorlabs 5x beam
expander and the Strachan Device. Using the Strachan Device, the 674 nm beam was adjusted
to the 80 percent phase cancellation level to achieve a power of approximately 0.48
mW over the 3 cm diameter beam. Both beams were electronically amplitude modulated
at 6.25 MHz
[0104] After the sequenced laser treatment, the lid of the glass Petri dish was removed,
and the solution allowed to dry through slow evaporation at a room temperature of
about 19 to 20°C and 32 percent humidity. The resultant material dried to a transparent
glass state. The laser treated atorvastatin calcium was then studied using PXRD, and
found to be non-crystalline. The PXRD pattern is illustrated in Figure 20.
[0105] The non-crystalline laser treated atorvastatin calcium was then analyzed with FTIR
spectroscopy. The FTIR spectrum obtained is illustrated in Figure 22. A comparison
of the FTIR spectrum of the non-crystalline atorvastatin calcium with the FTIR spectrum
of crystalline atorvastatin calcium, illustrated in Figure 21, demonstrates that the
laser treated material is atorvastatin calcium. The FTIR spectrum of the non-crystalline
laser treated atorvastatin calcium exhibits some broadening of the peaks compared
to the spectrum of the crystalline atorvastatin calcium, as expected for the non-crystalline
versus crystalline form of a compound.
[0106] Prior studies with atorvastatin calcium have made distinctions between the non-crystalline
states of this compound produced through different methods. While Form 23 was the
form originally tested by the original innovator, the most common non-crystalline
form produced in other labs is known as Form 27. Figure 23 compares the PXRD patterns
of Form 23 and Form 27, and shows that their broad bands of reflection are somewhat
different with Form 23 appearing more crystalline. This impression is further confirmed
with small angle X-ray scattering (SAXS) shown in Figure 24, demonstrating that Form
23 is more ordered. The PXRD of the sequenced laser treated atorvastatin calcium shown
in Figure 20 has a pattern that differs from the patterns obtained from Forms 23 and
27, suggesting it has the lowest level of residual crystallinity of any of the forms
examined.
[0107] Solubility studies with Forms 23 and 27 showed that during the first hour of dissolution,
the aqueous solubility of Form 23 was 3.2 times and that of Form 27 was 4.3 times
that of commercial crystalline atorvastatin calcium. By virtue of further reductions
in short range ordering, the highly non-crystalline glass form laser treated atorvastatin
calcium is predicted to show a further increment in solubility and bioavailability
over these two forms. This increment offers the advantage of potential dose reduction
with maintenance or augmentation of desired clinical effects and reduction or elimination
of adverse effects.
[0108] Further advantages of this method of producing highly non-crystalline glass atorvastatin
calcium over other methods includes applying only very low energies in acoustic resonance
with the system to reduce the tendency to thermal degradation or instability of the
compound and not requiring the use of environmentally toxic, harsh, or expensive solvents.
Residual solvent in the solid state would pose essentially no health risk compared
to other solvents in commercial use. Once desolvation occurs, the transparent glass
state appears to be very stable with negligible observed tendency to recrystallization,
increasing the practicality of large scale production and distribution.
Comparative Example: Atorvastatin Calcium
[0109] The protocol of Example 5 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the atorvastatin calcium obtained without the application
of the laser radiation is illustrated in Figure 60. The PXRD pattern of Figure 60
has the same peaks as that of the control sample illustrated in Figure 19. An FTIR
analysis of the resulting atorvastatin calcium was also performed, confirming the
material was atorvastatin calcium. The results demonstrate that the non-crystalline
atorvastatin calcium is not an artifact of the experiment, but, instead, is a direct
result of the application of the laser radiation in the process of the invention.
Example 6: Preparation of Non-crystalline Rosuvastatin Calcium
[0110] A control sample of reference standard rosuvastatin calcium was analyzed with PXRD
and FTIR spectroscopy. The PXRD spectrum obtained from the sample had the broad bands
of reflection characteristic of currently produced amorphous rosuvastatin calcium,
and is illustrated in Figure 25. The FTIR spectrum obtained from the sample of rosuvastatin
calcium is illustrated in Figure 27.
[0111] A 10 mg sample of rosuvastatin calcium reference compound was dissolved in 530 mg
of absolute ethanol by heating to 160°C while stirring at 9000 rpm for 12.5 minutes.
The solution was transferred into a 60 mm x 15 mm glass Petri dish, covered with a
glass lid, and placed on a hotplate at 95°C.
[0112] First, amplitude modulated diode laser light having a central wavelength of about
408 nm was applied to the solution of rosuvastatin calcium for 1 minute. Then amplitude
modulated diode laser light having a central wavelength of about 674 nm was applied
to the solution of rosuvastatin calcium for 1 minute. Those cycles were then followed
by another cycle of amplitude modulated laser light at 408 nm wavelength for 1 minute,
then another cycle of amplitude modulated laser light with 674 nm wavelength for 1
minute, followed by a final cycle of amplitude modulated laser light at 408 nm wavelength
for 30 seconds, then with another cycle of amplitude modulated laser light at 674
nm wavelength for 30 seconds. During these cycles, the sample was rotated slowly through
each of the approximately 3 cm diameter expanded beams at a distance of 25 cm from
the respective Strachan Devices. The emission from the 408 nm diode laser had a peak
power of 2.17 mW after passing through a Thorlabs 5x beam expander and the Strachan
Device. The output of the 408 nm beam was optically phase cancelled using the Strachan
Device to achieve a measured 80 percent reduction of transmitted power to 0.42 mW
over a 3 cm beam. The emission from the 674 nm diode laser was passed through a Thorlabs
5x beam expander and the Strachan Device. Using the Strachan Device, the 674 nm beam
was adjusted to the 80 percent phase cancellation level to achieve a power of approximately
0.48 mW over a 3 cm beam. Both beams were electronically amplitude modulated at 6.25
MHz
[0113] After the sequenced laser treatment the lid of the glass Petri dish was removed,
and the solution allowed to dry through slow evaporation at a room temperature of
about 20° to 21°C and about 35 percent humidity. The resultant material dried to a
transparent glass state. A PXRD analysis of the laser treated rosuvastatin illustrated
in Figure 26 is free of PXRD peaks characteristic of a crystalline compound, confirming
that that the laser treated rosuvastatin calcium is non-crystalline.
[0114] An FTIR spectrum of the laser treated rosuvastatin calcium spectroscopy is illustrated
in Figure 28. A comparison of the FTIR spectrum of the laser treated rosuvastatin
calcium with that of the reference solid state rosuvastatin calcium shown in Figure
27 confirms that the laser treated material is rosuvastatin calcium.
[0115] Comparing the PXRD patterns of solid state rosuvastatin calcium to laser treated
rosuvastatin, the broad reflection bands observed in solid state rosuvastatin calcium
are blunted or absent in laser treated rosuvastatin, suggesting an even greater reduction
of short range ordering in laser treated rosuvastatin As in the discussion for laser
treated atorvastatin calcium, the reduced residual crystallinity of laser treated
rosuvastatin calcium compared to untreated rosuvastatin calcium predicts that laser
treated rosuvastatin calcium will be more soluble and bioavailable than currently
produced solid state rosuvastatin calcium, though further testing is required to determine
whether this is sufficient to be clinically significant with respect to compound performance.
Example 7: Preparation of Co-amorphous Ezetimibe/Simvastatin
[0116] Highly intermixed non-crystalline blends of two of more compounds into a co-amorphous
glass state have been produced with the laser treatment of the present invention.
Comparative data for interpretation of results for the co-amorphous combinations was
obtained from the PXRD and FTIR analysis of separate untreated reference samples of
each of the ezetimibe and simvastatin and separate samples of ezetimibe and simvastatin
treated with the process of the invention. The PXRD pattern of the reference sample
of crystalline ezetimibe, having the characteristic PXRD peaks of a crystalline compound,
is illustrated in Figure 11, and the PXRD pattern of non-crystalline, laser treated
ezetimibe is illustrated in Figure 13. The PXRD pattern of the reference sample of
crystalline simvastatin is illustrated in Figure 7, and the PXRD pattern of laser
treated non-crystalline simvastatin is illustrated in Figure 9.
[0117] The FTIR spectrum of the reference sample of crystalline ezetimibe is illustrated
in Figure 12 with the FTIR spectrum of the non-crystalline laser treated ezetimibe.
The FTIR spectrum of the reference sample of crystalline simvastatin is illustrated
in Figure 8, and the FTIR spectrum of the non-crystalline laser treated simvastatin
is illustrated in Figure 10. As the PXRD pattern of a compound in the non-crystalline
state results in disappearance of characteristic deflection peaks, FTIR spectroscopy
allows compound identification and provides further evidence of the non-crystalline
state by showing a broadening of absorption bands that occurs in the non-crystalline
compared to the crystalline state.
[0118] Co-amorphous samples of ezetimibe and simvastatin were prepared with the process
of the invention with ezetimibe:simvastatin weight ratios of 1:1, 1:2, 1:4, and 1:8.
[0119] For an ezetimibe:simvastatin weight ratio of 1:1, 20 mg of crystalline ezetimibe
and 20 mg sample of crystalline simvastatin were dissolved in 753 mg of absolute ethanol
by stirring at 9000 rpm with a magnetic stirrer for 7.5 minutes, followed by stirring
at 9000 rpm for an additional 11 minutes on a heated plate at 140°C. The solution
was cooled to 20°C, and then filtered using a syringe to remove any residual crystals.
Half of the solution was then decanted into a 60 mm x 15 mm glass Petri dish covered
with a glass lid to provide approximately 10 mg of ezetimibe and 10 mg of simvastatin
in this sample.
[0120] For an ezetimibe:simvastatin weight ratio of 1:2, 10 mg of control crystalline ezetimibe
and 20 mg of crystalline simvastatin were dissolved in 698 mg of absolute ethanol,
and stirred at 9000 rpm with a magnetic stirrer for 8 minutes, followed by stirring
at 9000 rpm for an additional 10 minutes on a heated plate at 140°C. The solution
was cooled to approximately 20°C, and then filtered using a syringe to remove any
residual crystals. Half of the solution was then decanted into a 60 mm x 15 mm glass
Petri dish covered with a glass lid.
[0121] For an ezetimibe:simvastatin weight ratio of 1:4, 5 mg of crystalline ezetimibe and
20 mg crystalline simvastatin were dissolved in 663 mg of absolute ethanol, and stirred
at 9000 rpm for 8 minutes, followed by stirring at 9000 rpm for an additional 10 minutes
on a heated plate at 140°C. The solution was cooled to approximately 20°C, and then
filtered using a syringe to remove any residual crystals. Half of the solution was
then decanted into a 60 mm x 15 mm glass Petri dish covered with a glass lid
[0122] For an ezetimibe:simvastatin weight ratio of 1:8, 2.5 mg of crystalline ezetimibe
and 20 mg crystalline simvastatin were dissolved in 502 mg of absolute ethanol, and
stirred at 9000 rpm for 3 minutes, followed by stirring at 9000 rpm for an additional
11 minutes on a heated plate at 140°C. The solution was cooled to approximately 20°C,
and then filtered using a syringe to remove any residual crystals. Half of the solution
was then decanted into a 60 mm x 15 mm glass Petri dish covered with a glass lid
[0123] Those ezetimibe/simvastatin samples, having ezetimibe/simvastatin rations of 1:1,
1:2, 1:4, and 1:8, were first treated with amplitude modulated laser radiation from
a diode laser having a central wavelength of about 674 nm wavelength for 2.5 minutes,
and then with amplitude modulated laser radiation from a diode laser having a central
wavelength of about 408 nm for 2.5 minutes, rotating the sample slowly through each
of the approximately 3 cm diameter expanded beams at a distance of 25 cm from the
respective Strachan Devices. The 674 nm laser diode beam was passed through a Thorlabs
5x beam expander and a Strachan Device. Using the Strachan Device, the 674 nm beam
was adjusted to the 80 percent phase cancellation level to achieve a power of 0.48
mW over a 3 cm expanded beam. The 408 nm beam had a peak power of 0.10 mW after passing
through a Thorlabs 5x beam expander and the Strachan Device. The output of the 408
nm beam was optically phase cancelled using the Strachan Device to achieve a measured
80 percent reduction of transmitted power to 0.02 mW over a 3 cm expanded beam. Both
beams were electronically amplitude modulated at 6.25 Megahertz (MHz).
[0124] After the sequenced laser treatments of the solutions, the lids of the glass Petri
dishes were removed and the solutions were allowed to dry through slow evaporation
at a room temperature about of 20 to 21°C and about 40 to 43 percent humidity. The
resultant material for all four ezetimibe/simvastatin samples dried to a pure transparent
glass state. The ezetimibe/simvastatin samples, having ezetimibe/simvastatin ratios
of 1:1, 1:2, 1:4, and 1:8, were examined by polarizing light microscopy (PLM), and
all were found to appear entirely isotropic, indicating that all the treated samples
tested were non-crystalline, and, thus, co-amorphous.
[0125] Figure 29 illustrates the PXRD pattern of the sample of laser treated ezetimibe/simvastatin
in a 1:1 ratio by weight, demonstrating that the combination of ezetimibe and simvastatin
is non-crystalline. Figure 30 illustrates the PXRD pattern of the sample of laser
treated ezetimibe/simvastatin in a 1:2 ratio by weight, demonstrating that the combination
of ezetimibe and simvastatin is non-crystalline. Figure 31 illustrates the PXRD pattern
of the sample of laser treated ezetimibe/simvastatin in a 1:4 ratio by weight, demonstrating
that the combination of ezetimibe and simvastatin is non-crystalline. Figure 32 illustrates
the PXRD pattern of the sample of laser treated ezetimibe/simvastatin in a 1:8 ratio
by weight, demonstrating that the combination of ezetimibe and simvastatin is non-crystalline.
[0126] Thus, the process of the invention produced highly co-amorphous combinations of ezetimibe/simvastatin
in all four of the currently clinically used weight ratios of 1:1, 1:2, 1:4, and 1:8.
[0127] The process was them repeated first treating the solutions of ezetimibe and simvastatin
with the modified laser radiation from the 408 nm diode laser, followed by the modified
laser radiation from the 674 nm diode laser. During these tests, the second half of
the 1:1, 1:2, 1:4, and 1:8 weight ratio solutions described above were repeated with
the reverse laser application protocol. The sequenced laser treatments were identical
to those described above, except that the 2.5 minute application of the 408 nm diode
laser was applied prior to the 2.5 minute application of the modified emission of
the 674 nm laser diode.
[0128] Following the sequenced laser treatment, the lids of the glass Petri dishes were
removed, and the solutions were allowed to dry through slow evaporation at a temperature
of about 20° to about 22°C and about 40 to 47 percent humidity. The resultant material
for all four ezetimibe/simvastatin samples dried to a pure transparent glass state.
The ezetimibe/simvastatin samples, in ratios of 1:1, 1:2, 1:4, and 1:8 were examined
by polarizing light microscopy, and all were found to appear entirely isotropic, indicating
that all the treated samples were co-amorphous.
[0129] Figure 33 illustrates the PXRD pattern of sample laser treated ezetimibe/simvastatin
in a 1:1 weight ratio, demonstrating that the combination ezetimibe and simvastatin
is co-amorphous. Figure 34 illustrates the PXRD pattern of laser treated ezetimibe/simvastatin
in a 1:2 weight ratio, demonstrating that the combination of ezetimibe and simvastatin
co-amorphous. Figure 35 illustrates the PXRD pattern of laser treated ezetimibe/simvastatin
in a 1:4 weight ratio, demonstrating that the combination of ezetimibe and simvastatin
is co-amorphous. Figure 36 illustrates the PXRD pattern of laser treated ezetimibe/simvastatin
in a 1:8 ratio by weight, demonstrating that the combination of ezetimibe and simvastatin
is co-amorphous.
[0130] The co-amorphous combinations of ezetimibe/simvastatin were then analyzed using Fourier
transform infrared (FTIR) spectroscopy. Figure 37, Figure 38, Figure 39, and Figure
40 illustrate the FTIR spectra of the laser treated co-amorphous ezetimibe/simvastatin
samples having ratios of 1:1, 1:2, 1:4, and 1:8, respectively. Figure 41, Figure 42,
Figure 43, and Figure 44 illustrate the FTIR spectra of the laser treated co-amorphous
ezetimibe/simvastatin samples having ratios of 1:1, 1:2, 1:4, and 1:8, respectively.
The progression of compound ratios in each of these sequences is 1:1, 1:2, 1:4, and
1:8. The FTIR spectra of all of these ezetimibe/simvastatin combinations demonstrate
that both ezetimibe and simvastatin are present in the co-amorphous samples, and are
thoroughly mixed. There is some broadening of a few of the absorbance lines consistent
with a non-crystalline form for each of these samples. As the progression of compound
ratios becomes more predominant in simvastatin, the spectral bands of simvastatin
become relatively stronger than those of the ezetimibe, as would be anticipated for
the change in weight ratios in the compositions.
[0131] Once the co-amorphous glass combinations were produced through this method, they
appeared to be very stable at room temperature storage conditions with no observed
tendency to recrystallization. Given the ease of producing the highly non-crystalline
co-amorphous form of the different ratios used in this example, it is likely that
a wide range of additional ratios could be readily produced. With the observed ease
of producing and stabilizing the co-amorphous compositions of ezetimibe and simvastatin,
increasing production to the level of large scale manufacturing is expected to be
relatively straightforward.
Comparative Example: Ezetimibe/simvastatin
[0132] The protocol of Example 7 was repeated for each of the 1:1, 1:2, 1:4, and 1:8 weight
ratio ezetimibe/simvastatin samples with the exception that there was no application
of laser radiation. The resulting materials were visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for each of the 1:1, 1:2, 1:4, and 1:8 weight ratio ezetimibe/simvastatin
samples obtained without the application of the laser radiation are illustrated in
Figures 80, 81, 82, and 83, respectively. An FTIR analysis of each of the resulting
ezetimibe/simvastatin samples was also performed, confirming that each sample was
composed of ezetimibe and simvastatin. The results demonstrate that the co-amorphous
ezetimibe/simvastatin is not an artifact of the experiment, but, instead, is a direct
result of the application of the laser radiation in the process of the invention.
Example 8: Preparation of Co-amorphous Glass Ezetimibe/Atorvastatin Calcium
[0133] Comparative data for interpretation of results for the co-amorphous combinations
was obtained from the PXRD and FTIR analysis of separate untreated reference samples
of each of the ezetimibe and atorvastatin calcium and separate samples of ezetimibe
and atorvastatin calcium treated with the process of the invention. The PXRD pattern
of the reference crystalline ezetimibe is illustrated in Figure 11. The PXRD pattern
of laser treated non-crystalline ezetimibe is shown in Figure 13. The PXRD pattern
of crystalline atorvastatin calcium is illustrated in Figure 19. The PXRD pattern
of laser treated non-crystalline atorvastatin calcium is illustrated in Figure 20.
[0134] The FTIR spectrum of the reference crystalline ezetimibe is illustrated in Figure
12 with the FTIR spectrum of the non-crystalline laser treated ezetimibe. The FTIR
spectrum of the reference crystalline atorvastatin calcium is illustrated in Figure
21, and the FTIR spectrum of the non-crystalline laser treated atorvastatin calcium
is illustrated in Figure 22.
[0135] A 50 mg sample of crystalline ezetimibe and a 50 mg sample of crystalline atorvastatin
calcium were dissolved in 2008 mg of absolute ethanol by stirring at 9000 rpm with
a magnetic stirrer for 12.5 minutes on a heated plate at 140°C. The solution was then
cooled to room temperature, and filtered using a syringe to remove any residual crystals.
About 20 percent of the solution was then decanted into a 60 mm x 15 mm glass Petri
dish on a heated plate at 100°C, and covered with a glass lid to provide approximately
10 mg of ezetimibe and 10 mg of atorvastatin calcium in the treated sample, i.e.,
a 1:1 weight ratio.
[0136] The sample was first treated with amplitude modulated laser radiation from a diode
laser having a central wavelength of about 408 nm for 2.5 minutes, and then the sample
was treated with amplitude modulated laser radiation from a diode laser having a central
wavelength of about 674 nm for 2.5 minutes, rotating the sample slowly through each
of the approximately 3 cm diameter expanded beams at a distance of 25 cm from the
respective Strachan Devices. The 408 nm laser diode beam had a peak power of 0.88
mW after passing through a Thorlabs 5x beam expander and the Strachan Device. Using
the Strachan Device, the 408 nm beam was adjusted to the 80 percent phase cancellation
level to achieve a measured power of 0.17 mW over the 3 cm beam. The 674 nm beam was
passed through a Thorlabs 5x beam expander and a Strachan Device. The output of the
674 nm beam was optically phase cancelled using the Strachan Device to achieve a measured
80 percent reduction of transmitted power to approximately 0.48 mW over the 3 cm beam.
Both beams were electronically amplitude modulated at 6.25 MHz.
[0137] After the sequenced laser treatment, the lid of the glass Petri dish was removed,
and the solution was allowed to dry through slow evaporation at a temperature of about
22°C and 24 percent humidity. The resultant ezetiinibe/atorvastatin sample dried to
a pure transparent glass state. Figure 45 illustrates the PXRD pattern of the laser
treated ezetimibe/atorvastatin calcium in a 1:1 weight ratio, demonstrating that the
combination of ezetimibe and atorvastatin calcium is non-crystalline.
[0138] The co-amorphous ezetimibe/atorvastatin calcium composition was then subjected to
an FTIR analysis. Figure 46 illustrates the FTIR spectrum of the laser treated ezetimibe/atorvastatin
calcium in a 1:1 ratio, demonstrating that both ezetimibe and atorvastatin calcium
are present and thoroughly mixed. There is some broadening of a few of the absorbance
lines consistent with the non-crystalline form of each of the compounds.
[0139] The co-amorphous combination of ezetimibe/atorvastatin in the 1:1 ratio was found
to be very stable at room temperature storage conditions with no observed tendency
to recrystallization. Given the ease of producing the highly non-crystalline co-amorphous
glass form of this combination of compounds and the non-crystalline glass form of
each compound individually, it is likely that a wide range of additional ratios could
readily be produced. With the observed ease of producing and stabilizing of the co-amorphous
form of this combination of compounds, incrementally increasing production up to the
level of large scale manufacturing is expected to be readily accomplished through
replication of application modules of this method.
Comparative Example: Ezetimibe/Atorvastatin Calcium
[0140] The protocol of Example 8 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the ezetimibe/atorvastatin calcium obtained without
the application of the laser radiation is illustrated in Figure 61. The PXRD pattern
of Figure 61 has peaks that correspond to PXRD peaks for ezetimibe and atorvastatin
calcium illustrated in Figures 11 and 19. An FTIR analysis of the resulting ezetimibe/atorvastatin
calcium was also performed, confirming that the material was ezetimibe and atorvastatin
calcium. The results demonstrate that the co-amorphous ezetimibe/atorvastatin calcium
is not an artifact of the experiment, but, instead, is a direct result of the application
of the laser radiation in the process of the invention.
Example 9: Preparation of Co-amorphous Ezetimibe/Atorvastatin Free Acid
[0141] Comparative data for interpretation of results for the co-amorphous combinations
was obtained from the PXRD and FTIR analysis of separate untreated reference samples
of each of the ezetimibe and atorvastatin free acid and separate samples of ezetimibe
and atorvastatin free acid treated with the process of the invention. The PXRD pattern
of the reference crystalline ezetimibe is illustrated in Figure 11. The PXRD pattern
of laser treated non-crystalline ezetimibe is shown in Figure 13. The PXRD pattern
of crystalline atorvastatin free acid is illustrated in Figure 15. The PXRD pattern
of laser treated non-crystalline atorvastatin free acid is shown in Figure 16.
[0142] The spectrum obtained from the FTIR analysis of the reference sample of crystalline
ezetimibe is illustrated in Figure 12 with the FTIR spectrum of the laser treated
non-crystalline ezetimibe. The FTIR spectrum of crystalline atorvastatin free acid
is illustrated in Figure 17, and the FTIR spectrum of non-crystalline laser treated
atorvastatin free acid is illustrated in Figure 18.
[0143] A 50 mg sample of crystalline ezetimibe and a 50 mg sample of crystalline atorvastatin
free acid were dissolved in 1999 mg of absolute ethanol by stirring at 9000 rpm with
a magnetic stirrer for 12.5 minutes on a heated plate at 140°C. The solution was then
cooled to room temperature, and filtered using a syringe to remove any residual crystals.
About 20 percent of the solution was then decanted into a 60 mm x 15 mm glass Petri
dish on a heated plate at 100°C, and covered with a glass lid to provide a solution
of approximately 10 mg of ezetimibe and 10 mg of atorvastatin free acid, i.e., a 1:1
weight ratio of ezetimibe and atorvastatin free acid.
[0144] The sample of ezetimibe/atorvastatin free acid was first treated with amplitude modulated
laser radiation from a diode laser having a central wavelength of about 674 nm for
2.5 minutes, and then with amplitude modulated laser radiation from a diode laser
having a central wavelength of about 408 nm for 2.5 minutes, rotating the sample slowly
through each of the approximately 3 cm diameter expanded beams at a distance of 25
cm from the respective Strachan Devices. The 674 nm laser diode beam was passed through
a Thorlabs 5x beam expander and a Strachan Device. Using the Strachan Device, the
674 nm beam was adjusted to the 80 percent phase cancellation level to achieve a power
of approximately 0.48 mW over a 3 cm beam. The 408 nm beam had a peak power of 0.88
mW after passing through a Thorlabs 5x beam expander and the Strachan Device. The
output of the 408 nm beam was optically phase cancelled using the Strachan Device
to achieve a measured 80 percent reduction of transmitted power to 0.17 mW over a
3 cm beam. Both beams were electronically amplitude modulated at 6.25 MHz.
[0145] After the sequenced laser treatment the lid of the glass Petri dish was removed,
and the solution was allowed to dry through slow evaporation at a temperature of about
22° to 23°C and about 20 percent humidity. The resultant sample of ezetimibe and atorvastatin
free acid dried to a pure transparent glass state. Figure 47 illustrates the PXRD
pattern of laser treated ezetimibe/atorvastatin free acid in a 1:1 weight ratio, demonstrating
that combination of ezetimibe and atorvastatin free acid is non-crystalline.
[0146] The co-amorphous composition of ezetimibe and atorvastatin free acid was analyzed
with FTIR spectroscopy. Figure 48 illustrates the FTIR spectrum of the laser treated
ezetimibe/atorvastatin free acid, indicating that that both compounds are present
and are thoroughly mixed in the co-amorphous composition. There is some broadening
of a few of the absorbance lines consistent with a non-crystalline form of each compound
in the co-amorphous composition.
[0147] The co-amorphous ezetimibe/atorvastatin free acid composition, having a 1:1 weight
ratio was found to be very stable at room temperature storage conditions with no observed
tendency to recrystallize. Given the ease of producing the co-amorphous composition
of ezetimibe and atorvastatin free acid, it is likely that a wide range of additional
ratios could be produced readily. With the observed ease of producing and stabilizing
of the co-amorphous form of this combination of compounds, incrementally increasing
production up to the level of large scale manufacturing is expected to be readily
accomplished through replication of application modules of this method.
Comparative Example: Ezetimibe/Atorvastatin Free Acid
[0148] The protocol of Example 8 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the ezetimibe/atorvastatin calcium obtained without
the application of the laser radiation is illustrated in Figure 62. The PXRD pattern
of Figure 62 has the peaks that correspond to PXRD peaks for ezetimibe and atorvastatin
free acid illustrated in Figures 11 and 15. An FTIR analysis of the resulting ezetimibe/atorvastatin
free acid was also performed, confirming the material was ezetimibe and atorvastatin
free acid. The results demonstrate that the co-amorphous ezetimibe/atorvastatin free
acid is not an artifact of the experiment, but, instead, is a direct result of the
application of the laser radiation in the process of the invention.
Example 10: Preparation of Co-amorphous Ezetimibe/Rosuvastatin Calcium
[0149] Comparative data for interpretation of results for the co-amorphous combinations
was obtained from the PXRD and FTIR analysis of untreated reference samples of each
of the ezetimibe and rosuvastatin calcium and samples of ezetimibe and rosuvastatin
calcium treated with the process of the invention. The PXRD pattern of the reference
crystalline ezetimibe is illustrated in Figure 11. The PXRD pattern of laser treated
non-crystalline ezetimibe is shown in Figure 13. The PXRD pattern of the reference
sample of amorphous rosuvastatin calcium is illustrated in Figure 25, and the PXRD
pattern of the laser treated non-crystalline rosuvastatin calcium is illustrated in
Figure 26.
[0150] The FTIR spectrum of the reference crystalline ezetimibe is illustrated in Figure
12 with the FTIR spectrum of the laser treated non-crystalline ezetimibe. The FTIR
spectrum of the reference sample of rosuvastatin calcium is illustrated in Figure
27, and the FTIR spectrum of the non-crystalline laser treated rosuvastatin calcium
is illustrated Figure 28.
[0151] A 10 mg sample of crystalline ezetimibe and a 10 mg sample of rosuvastatin calcium
were dissolved in 408 mg of absolute ethanol by stirring at 9000 rpm with a magnetic
stirrer for 8 minutes, followed by stirring at 9000 rpm with a magnetic stirrer for
an additional 10 minutes on a heated plate at 140°C. The solution was decanted into
a 60 mm x 15 mm glass Petri dish on a heated plate at 100°C, and covered with a glass
lid to provide approximately 10 mg of ezetimibe and 10 mg of atorvastatin free acid
in the solution, i.e., a 1:1 weight ratio.
[0152] The ezetimibe/rosuvastatin sample was treated first with amplitude modulated laser
radiation from a diode laser having a central wavelength of about 674 nm wavelength
for 2.5 minutes, then with amplitude modulated laser radiation from a diode laser
having a central wavelength of about 408 nm for 2.5 minutes, rotating the sample slowly
through each of the approximately 3 cm diameter expanded beams at a distance of 25
cm from the respective Strachan Devices. The 674 nm laser diode beam was passed through
a Thorlabs 5x beam expander and a Strachan Device. Using the Strachan Device, the
674 nm beam was adjusted to the 80 percent phase cancellation level to achieve a power
of approximately .048 mW over a 3 cm diameter beam. The 408 nm beam had a peak power
of 2.15 mW after passing through a Thorlabs 5x beam expander and the Strachan Device.
The output of the 408 nm beam was optically phase cancelled using the Strachan Device
to achieve a measured 80 percent reduction of transmitted power to 0.43 mW over a
3 cm diameter beam. Both beams were electronically amplitude modulated at 6.25 MHz.
[0153] After the sequenced laser treatment of the ezetimibe and rosuvastatin calcium, the
lid of the glass Petri dish was removed, and the solution was allowed to dry through
slow evaporation at a temperature of 19°C and 45 percent humidity. The resultant material
for the sample of ezetimibe/rosuvastatin dried to a pure transparent glass state.
Figure 49 illustrates the PXRD pattern of the laser treated ezetimibe/rosuvastatin
in a 1:1 weight ratio, demonstrating that the combination of ezetimibe and rosuvastatin
calcium is non-crystalline.
[0154] The co-amorphous composition of ezetimibe and rosuvastatin calcium was then analyzed
with FTIR spectroscopy. Figure 50 illustrates the FTIR spectrum of the laser treated
ezetimibe/rosuvastatin, demonstrating that both ezetimibe and rosuvastatin calcium
compounds are present in the composition and thoroughly mixed. There is also some
broadening of a few of the absorbance lines consistent with a non-crystalline form
for each of the compounds.
[0155] The ezetimibe/rosuvastatin calcium composition in a 1:1 weight ratio was found to
be very stable at room temperature storage conditions with no observed tendency to
recrystallize. Given the ease of producing the co-amorphous form of the ezetimibe/rosuvastatin
calcium composition and the non-crystalline glass form of each compound individually,
it is likely that a wide range of additional ratios could readily be produced. With
the observed ease of producing and stabilizing of the co-amorphous ezetimibe and rosuvastatin
calcium, scaling production up to the level of large scale manufacturing is expected
to be readily accomplished through replication of application modules of this method.
Comparative Example: Ezetimibe/Rosuvastatin Calcium
[0156] The protocol of Example 10 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the ezetimibe/rosuvastatin calcium obtained without
the application of the laser radiation is illustrated in Figure 63. The PXRD pattern
of Figure 63 has the peaks that correspond to PXRD peaks for ezetimibe and rosuvastatin
calcium illustrated in Figures 11 and 25. An FTIR analysis of the resulting ezetimibe/rosuvastatin
calcium was also performed, confirming the material was ezetimibe and rosuvastatin
calcium. The results demonstrate that the co-amorphous ezetimibe/rosuvastatin calcium
is not an artifact of the experiment, but, instead, is a direct result of the application
of the laser radiation in the process of the invention.
Example 11: Preparation of Co-amorphous Ezetimibe/Simvastatin/Aspirin
[0157] Comparative data for interpretation of results for the co-amorphous combinations
was obtained from the PXRD and FTIR analysis of untreated reference samples of each
of the ezetimibe, simvastatin, and aspirin and samples of ezetimibe, simvastatin,
and aspirin treated with the process of the invention. The PXRD pattern of the reference
crystalline ezetimibe is illustrated in Figure 11. The PXRD pattern of laser treated
non-crystalline ezetimibe is shown in Figure 13. The PXRD pattern of crystalline simvastatin
is illustrated in Figure 7. The PXRD pattern of laser treated non-crystalline simvastatin
is illustrated in Figure 9. The PXRD pattern of crystalline aspirin is illustrated
in Figure 1. The PXRD pattern of laser treated non-crystalline aspirin is illustrated
in Figure 3.
[0158] The FTIR spectrum of crystalline ezetimibe is illustrated in Figure 12 with the FTIR
spectrum of non-crystalline laser treated ezetimibe. The FTIR spectrum of the reference
sample of crystalline simvastatin is illustrated in Figure 8. The FTIR spectrum of
the laser treated non-crystalline simvastatin is illustrated in Figure 10. The FTIR
spectrum of crystalline aspirin is illustrated in Figure 2. The FTIR spectrum of non-crystalline
laser treated aspirin is illustrated in Figure 4.
[0159] A 10 mg sample of crystalline ezetimibe, a 10 mg sample of crystalline simvastatin,
and a 5 mg sample of crystalline aspirin were dissolved in 1000 mg of absolute ethanol
by stirring at 9000 rpm with a magnetic stirrer for 12 minutes on a heated plate at
140°C. The solution was then cooled to room temperature, and filtered using a syringe
to remove any residual crystals. The solution was then decanted into a 60 mm x 15
mm glass Petri dish, and covered with a glass lid to provide 10 mg of ezetimibe, 10
mg of simvastatin, and 5 mg of aspirin in the sample of ezetimibe/simvastatin/aspirin;
i.e., a 2:2:1 weight ratio.
[0160] The sample of ezetimibe/simvastatin/aspirin was first treated with amplitude modulated
laser radiation from a diode laser having a central wavelength of about 408 nm for
2.5 minutes, and then with amplitude modulated laser radiation from a diode laser
having a central wavelength of about 674 nm for 2.5 minutes, rotating the sample slowly
through each of the approximately 3 cm diameter expanded beams at a distance of 25
cm from the respective Strachan Devices. The 408 nm laser diode beam had a peak power
of 2.61 mW after passing through a Thorlabs 5x beam expander and the Strachan Device.
Using the Strachan Device, the 408 nm beam was adjusted to the 80 percent phase cancellation
level to achieve a power of approximately 0.52 mW over a 3 cm diameter beam. The 674
nm beam was passed through a Thorlabs 5x beam expander and a Strachan Device. The
output of the 674 nm beam was optically phase cancelled using the Strachan Device
to achieve a measured 80 percent reduction of transmitted power to approximately 0.48
mW over a 3 cm diameter beam. Both beams were electronically amplitude modulated at
6.25 MHz.
[0161] After the sequenced laser treatment, the lid of the glass Petri dish was removed,
and the solution was allowed to dry through slow evaporation at a temperature of 21
°C and 26 percent humidity. The resultant material for the ezetimibe/simvastatin/aspirin
sample dried to a pure transparent glass state. Figure 51 illustrates the PXRD pattern
of the laser treated ezetimibe/simvastatin/aspirin in a 2:2:1 weight ratio, demonstrating
the composition of ezetimibe, simvastatin, and aspirin is non-crystalline.
[0162] The co-amorphous composition of ezetimibe, simvastatin, and aspirin was then analyzed
using FTIR spectroscopy. Figure 52 illustrates the FTIR spectrum of the co-amorphous
laser treated ezetimibe/simvastatin/aspirin composition, demonstrating that indicate
that all three compounds are present and thoroughly mixed. There is also some broadening
of a few of the absorbance lines consistent with a non-crystalline form.
[0163] The co-amorphous glass composition of ezetimibe/simvastatin/aspirin in a 2:2:1 weight
ratio was found to be very stable at room temperature storage conditions with no observed
tendency to recrystallize. With the observed ease of producing and stabilizing of
the co-amorphous form of this combination of compounds, scale up of manufacturing
is expected to be readily accomplished.
Comparative Example: Ezetimibe/Simvastatin/Aspirin
[0164] The protocol of Example 11 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the ezetimibe/simvastatin/aspirin obtained without
the application of the laser radiation is illustrated in Figure 68. The PXRD pattern
of Figure 68 has the peaks that correspond to PXRD peaks for ezetimibe, simvastatin,
and aspirin illustrated in Figures 11, 8, and 1. An FTIR analysis of the resulting
ezetimibe/simvastatin/aspirin was also performed, confirming that the crystalline
material was ezetimibe, simvastatin, and aspirin. The results demonstrate that the
co-amorphous ezetimibe/simvastatin/aspirin is not an artifact of the experiment, but,
instead, is a direct result of the application of the laser radiation in the process
of the invention.
Example 12: Preparation of Co-amorphous Ezetimibe/Atorvastatin Calcium/Aspirin
[0165] Comparative data for interpretation of results for the co-amorphous combinations
was obtained from the PXRD and FTIR analysis of untreated reference samples of each
of the ezetimibe and atorvastatin calcium and aspirin and the non-crystalline forms
of these compounds treated with the process of the invention. The PXRD pattern of
the reference crystalline ezetimibe is illustrated in figure 11. The PXRD pattern
of laser treated non-crystalline ezetimibe is shown in Figure 13. The PXRD pattern
of crystalline atorvastatin calcium is illustrated in Figure 19. The PXRD pattern
of laser treated non-crystalline atorvastatin calcium is illustrated in Figure 20.
The PXRD pattern of crystalline aspirin is illustrated in Figure 1. The PXRD pattern
of laser treated non-crystalline aspirin is illustrated in Figure 3.
[0166] The FTIR spectrum of the reference crystalline ezetimibe is illustrated in Figure
12 with the FTIR spectrum of non-crystalline laser treated ezetimibe. The FTIR spectrum
of the reference sample of crystalline atorvastatin calcium is illustrated in Figure
21. The FTIR spectrum of non-crystalline laser treated atorvastatin calcium is illustrated
in Figure 22. The FTIR spectrum of the reference sample of crystalline aspirin is
illustrated in Figure 2. The FTIR spectrum of non-crystalline laser treated aspirin
is illustrated in Figure 4.
[0167] A 50 mg sample of crystalline ezetimibe, a 50 mg sample of crystalline atorvastatin
calcium, and a 25 mg sample of crystalline aspirin were dissolved in 2400 mg of absolute
ethanol by stirring at 9000 rpm with a magnetic stirrer for 12 minutes on a heated
plate at 140°C. The solution was then cooled to room temperature, and filtered using
a syringe to remove any residual crystals. Then, 20 percent of the solution was decanted
into a 60 mm x 15 mm glass Petri dish, and covered with a glass lid to provide 10
mg of ezetimibe, 10 mg of atorvastatin calcium, and 5 mg of aspirin in this sample
of ezetimibe/atorvastatin calcium/aspirin, i.e., a 2:2:1 weight ratio.
[0168] The ezetimibe, atorvastatin calcium, and aspirin were first treated with amplitude
modulated laser radiation from a diode laser emitting at a central wavelength of about
408 nm for 2.5 minutes, and then with amplitude modulated laser radiation from a diode
laser emitting at a central wavelength of about 674 nm wavelength for 2.5 minutes,
rotating the sample slowly through each of the approximately 3 cm diameter expanded
beams at a distance of 25 cm from the Strachan Device. The 408 nm laser diode beam
had a peak power of 0.71 mW after passing through a Thorlabs 5x beam expander and
the Strachan Device. Using the Strachan Device, the 408 nm beam was adjusted to the
80 percent phase cancellation level to achieve a measured power of 0.14 mW. The 674
nm beam was passed through a Thorlabs 5x beam expander and the Strachan Device. The
output of the 674 nm beam was optically phase cancelled using the Strachan Device
to achieve a measured 80 percent reduction of transmitted power to 0.48 mW over a
3 cm diameter beam. Both beams were electronically amplitude modulated at 6.25 MHz.
[0169] After the sequenced laser treatment, the lid of the glass Petri dish was removed,
and the solution was allowed to dry through slow evaporation at a room temperature
of about 20° to 21°C and 34 percent humidity. The resultant ezetimibe/atorvastatin
calcium/aspirin composition dried to a pure transparent glass state. Figure 53 illustrates
the PXRD pattern of the laser treated ezetimibe/atorvastatin calcium/aspirin in a
2:2:1 weight ratio to demonstrate that the combination of ezetimibe, atorvastatin
calcium, and aspirin was non-crystalline.
[0170] The co-amorphous ezetimibe/atorvastatin calcium/aspirin composition was then analyzed
using FTIR spectroscopy. Figure 54 illustrates the FTIR spectroscopic pattern of the
laser treated ezetimibe/atorvastatin calcium/aspirin, demonstrating that all three
compounds are present and are thoroughly mixed. There is also some broadening of a
few of the absorbance lines consistent with a non-crystalline form.
[0171] The 2:2:1 weight ratio ezetimibe/simvastatin/aspirin composition found to be very
stable at room temperature storage conditions with no observed tendency to recrystallization.
With the observed ease of producing and stabilizing of the co-amorphous form of this
combination of compounds, increasing production up to the level of large scale manufacturing
is expected to be readily accomplished through replication of application modules
of this method.
Comparative Example: Ezetimibe/Atorvastatin Calcium/Aspirin
[0172] The protocol of Example 12 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the ezetimibe/atorvastatin calcium/aspirin obtained
without the application of the laser radiation is illustrated in Figure 62. The PXRD
pattern of Figure 64 has the peaks that correspond to PXRD peaks for ezetimibe, atorvastatin
calcium, and aspirin illustrated in Figures 11, 19, and 1. An FTIR analysis of the
resulting ezetimibe/atorvastatin calcium/aspirin was also performed, confirming the
material was ezetimibe, atorvastatin calcium, and aspirin. The results demonstrate
that the co-amorphous ezetimibe/atorvastatin calcium/aspirin is not an artifact of
the experiment, but, instead, is a direct result of the application of the laser radiation
in the process of the invention.
Example 13: Preparation of Co-Amorphous Ezetimibe/Atorvastatin Free Acid/Aspirin
[0173] Comparative data for interpretation of results for the co-amorphous combinations
was obtained from the PXRD and FTIR analysis of untreated reference samples of each
of the ezetimibe and atorvastatin free acid and aspirin and the non-crystalline form
of these compounds treated with the process of the invention. The PXRD pattern of
the reference crystalline ezetimibe is illustrated in Figure 11. The PXRD pattern
of laser treated non-crystalline ezetimibe is shown in Figure 13. The PXRD pattern
of crystalline atorvastatin free acid is illustrated in Figure 15. The PXRD pattern
of the non-crystalline laser treated atorvastatin free acid is illustrated in Figure
16. The PXRD pattern of the crystalline aspirin is illustrated in Figure 1. The PXRD
pattern of laser treated non-crystalline aspirin is illustrated in Figure 3.
[0174] The FTIR spectrum of the reference sample of crystalline ezetimibe is illustrated
in Figure 12 with the FTIR spectrum of non-crystalline laser treated ezetimibe. The
FTIR spectrum of the reference sample of crystalline atorvastatin free acid is illustrated
in Figure 17. The FTIR spectrum of non-crystalline laser treated atorvastatin free
acid is illustrated in Figure 18. The FTIR spectrum of the reference sample of crystalline
aspirin is illustrated in Figure 2. The FTIR spectrum of non-crystalline laser treated
aspirin is illustrated in Figure 4.
[0175] A 50 mg sample of crystalline ezetimibe, a 50 mg sample of crystalline atorvastatin
free acid, and a 25 mg sample of crystalline aspirin were dissolved in 2400 mg of
absolute ethanol by stirring at 9000 rpm with a magnetic stirrer for 12 minutes at
on a heated plate at 140°C. The solution was then cooled to room temperature, and
filtered using a syringe to remove any residual crystals. 20 percent of this solution
was then decanted into a 60 mm x 15 mm glass Petri dish and covered with a glass lid
to provide 10 mg of ezetimibe, 10 mg of atorvastatin free acid, and 5 mg of aspirin
in this sample of ezetimibe/atorvastatin free acid/aspirin, i.e., a 2:2:1 weight ratio.
[0176] The ezetimibe, atorvastatin free acid, and aspirin were first treated with amplitude
modulated laser radiation emitted from a diode laser having a central wavelength of
about 408 for 2.5 minutes, and then with amplitude modulated laser radiation emitted
from a diode laser having a central wavelength of about 674 nm for 2.5 minutes, rotating
the sample slowly through each of the approximately 3 cm diameter expanded beams at
a distance of 25 cm from the Strachan Device. The 408 nm laser diode beam had a peak
power of 0.71 mW after passing through a Thorlabs 5x beam expander and the Strachan
Device. Using the Strachan Device, the 408 nm beam was adjusted to the 80 percent
phase cancellation level to achieve a measured power of 0.14 mW. The 674 nm beam was
passed through a Thorlabs 5x beam expander and the Strachan Device. The output of
the 674 nm beam was optically phase cancelled using the Strachan Device to achieve
a measured 80 percent reduction of transmitted power to 0.48 mW over a 3 cm diameter
beam. Both beams were electronically amplitude modulated at 6.25 MHz.
[0177] After the sequenced laser treatment, the lid of the glass Petri dish was removed,
and the solution was allowed to dry through slow evaporation at a temperature of 20°C
and 35 percent humidity. The resultant ezetimibe/atorvastatin free acid/aspirin composition
dried to a pure transparent glass state. Figure 55 illustrates the PXRD pattern of
the co-amorphous laser treated ezetimibe/atorvastatin free acid/aspirin in a 2:2:1
weight ratio, demonstrating that the composition is non-crystalline.
[0178] The co-amorphous ezetimibe/simvastatin/aspirin composition was then analyzed using
FTIR spectroscopy. Figure 56 illustrates the FTIR spectrum of the co-amorphous laser
treated ezetimibe/atorvastatin free acid/aspirin composition, confirming that all
three compounds are present and thoroughly mixed. There is also some broadening of
a few of the absorbance lines consistent with a non-crystalline form.
[0179] The co-amorphous ezetimibe/simvastatin/aspirin composition in a 2:2:1 weight ratio
was found to be very stable at room temperature storage conditions with no observed
tendency to recrystallization. Given the ease of producing the highly non-crystalline
co-amorphous form of this combination, it is likely that a wide range of additional
ratios could readily be produced. With the observed ease of producing and stabilizing
of the co-amorphous form of this combination of compounds, incrementally increasing
production up to the level of large scale manufacturing is expected to be readily
accomplished through replication of application modules of this method.
Comparative Example: Ezetimibe/Atorvastatin Free Acid/Aspirin
[0180] The protocol of Example 13 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the ezetimibe/atorvastatin free acid/aspirin obtained
without the application of the laser radiation is illustrated in Figure 65. The PXRD
pattern of Figure 65 has the peaks that correspond to PXRD peaks for ezetimibe, atorvastatin
free acid, and aspirin illustrated in Figures 11, 15, and 1. An FTIR analysis of the
resulting ezetimibe/atorvastatin free acid/aspirin was also performed, confirming
the material was ezetimibe, atorvastatin free acid, and aspirin. The results demonstrate
that the co-amorphous ezetimibe/atorvastatin free acid/aspirin is not an artifact
of the experiment, but, instead, is a direct result of the application of the laser
radiation in the process of the invention.
Example 14: Preparation of Co-Amorphous Ezetimibe/Rosuvastatin Calcium/Aspirin
[0181] Comparative data for interpretation of results for the co-amorphous combinations
was obtained from the PXRD and FTIR analysis of untreated reference samples of each
of the ezetimibe and rosuvastatin calcium and aspirin and the non-crystalline forms
of these compounds treated with the process of the invention. The PXRD pattern of
the reference crystalline ezetimibe is illustrated in Figure 11. The PXRD pattern
of laser treated non-crystalline ezetimibe is shown in Figure 13. The PXRD pattern
of the reference sample of rosuvastatin calcium is illustrated in Figure 25. The PXRD
pattern of laser treated non-crystalline rosuvastatin calcium is illustrated in Figure
26. The PXRD pattern of the reference sample of crystalline aspirin is illustrated
in Figure 1. The PXRD pattern of laser treated non-crystalline aspirin is illustrated
in Figure 3.
[0182] The FTIR spectrum of the reference sample of crystalline ezetimibe is illustrated
in Figure 12 with the FTIR spectrum of non-crystalline laser treated ezetimibe. The
FTIR spectrum of the reference sample of rosuvastatin calcium is illustrated in Figure
27. The FTIR spectrum of non-crystalline laser treated rosuvastatin calcium is illustrated
in Figure 28. The FTIR spectrum of the reference sample of crystalline aspirin is
illustrated in Figure 2. The FTIR spectrum of non-crystalline laser treated aspirin
is illustrated in Figure 4.
[0183] A 20 mg sample of crystalline ezetimibe, a 20 mg sample of rosuvastatin calcium,
and a 10 mg sample of crystalline aspirin were dissolved in 2000 mg of absolute ethanol
by stirring at 9000 rpm with a magnetic stirrer for 12 minutes on a heated plate at
140°C. The solution was then cooled to room temperature, and filtered using a syringe
to remove any residual crystals. Half of the solution was then decanted into a 60
mm x 15 mm glass Petri dish, and covered with a glass lid to provide a solution of
10 mg of ezetimibe, 10 mg of rosuvastatin calcium, and 5 mg of aspirin, i.e., a 2:2:1
weight ratio.
[0184] The ezetimibe/rosuvastatin calcium/aspirin solution was first treated with amplitude
modulated laser radiation from a diode laser having a central wavelength of about
408 nm 2.5 minutes, and then with amplitude modulated laser radiation from a diode
laser having a central wavelength of about 674 nm for 2.5 minutes, rotating the sample
slowly through each of the approximately 3 cm diameter expanded beams at a distance
of 25 cm from the respective Strachan Device. The 408 nm laser diode beam had a peak
power of 2.4 mW after passing through a Thorlabs 5x beam expander and the Strachan
Device. Using the Strachan Device, the 408 nm beam was adjusted to the 80 percent
phase cancellation level to achieve a measured power of 0.48 mW. The 674 nm beam was
passed through a Thorlabs 5x beam expander and the Strachan Device. The output of
the 674 nm beam was optically phase cancelled using the Strachan Device to achieve
a measured 80 percent reduction of transmitted power to 0.48 mW over a 3 cm diameter
beam. Both beams were electronically amplitude modulated at 6.25 MHz.
[0185] After the laser treatment, the lid of the glass Petri dish was removed, and the solution
was allowed to dry through slow evaporation at a temperature of 21 °C and 30 percent
humidity. The resultant co-amorphous ezetimibe/rosuvastatin calcium/aspirin composition
dried to a pure transparent glass state. Figure 57 illustrates the PXRD pattern of
laser treated co-amorphous ezetimibe/rosuvastatin calcium/aspirin composition in a
2:2:1 weight ratio, demonstrating that the composition is non-crystalline.
[0186] The co-amorphous ezetimibe/rosuvastatin calcium/aspirin composition was then analyzed
using FTIR spectroscopy. Figure 58 illustrates the FTIR spectrum of the laser treated
co-amorphous ezetimibe/rosuvastatin calcium/aspirin composition, indicating that all
three compounds are present and are thoroughly mixed. There is also some broadening
of a few of the absorbance lines consistent with a non-crystalline form.
[0187] The co-amorphous ezetimibe/rosuvastatin calcium/aspirin composition in a2:2:1 weight
was found to be very stable at room temperature storage conditions with no observed
tendency to recrystallize. With the observed ease of producing and stabilizing of
the co-amorphous form of this combination of compounds, incrementally increasing production
up to the level of large scale manufacturing is expected to be readily accomplished
through replication of application modules of this method.
Comparative Example: Ezetimibe/Rosuvastatin Calcium/Aspirin
[0188] The protocol of Example 13 was repeated with the exception that there was no application
of laser radiation. The resulting material was visibly crystalline, which was confirmed
by PXRD analysis, which demonstrated that a substantial amount of crystalline material
was present. A PXRD pattern for the ezetimibe/rosuvastatin calcium/aspirin obtained
without the application of the laser radiation is illustrated in Figure 66. The PXRD
pattern of Figure 66 has the peaks that correspond to PXRD peaks for ezetimibe, rosuvastatin
calcium, and aspirin illustrated in Figures 11, 25, and 1. An FTIR analysis of the
resulting ezetimibe/rosuvastatin calcium/aspirin was also performed, confirming the
material was ezetimibe, rosuvastatin calcium, and aspirin. The results demonstrate
that the co-amorphous ezetimibe/rosuvastatin calcium/aspirin is not an artifact of
the experiment, but, instead, is a direct result of the application of the laser radiation
in the process of the invention.
Example 15: Preparation of Non-Crystalline Atorvastatin Calcium/Aspirin
[0189] The highly non-crystalline glass state of the combination of atorvastatin calcium
and aspirin was produced by applying a sequence of long wavelength followed by short
wavelength laser light modulated and structured by a Strachan Device. A 60 mg sample
of crystalline atorvastatin calcium and a 60 mg sample of crystalline aspirin were
dissolved in 1000 mg of absolute ethanol by stirring at 9000 rpm with a magnetic stirrer,
while heating to 140°C for 10 minutes in a stoppered Erlenmeyer flask. The solution
was divided equally into six 60 mm x 15 mm glass Petri dishes for producing treated
and untreated control samples, and each sample was covered with a glass lid. The samples
were allowed to cool to room temperature.
[0190] One sample of atorvastatin calcium/aspirin in a 1:1 ratio by weight was treated with
a sequence of laser radiation modified with a Strachan Device. The first application
of amplitude modulated diode laser light was from a diode laser having a central wavelength
of 674 nm. The second application of amplitude modulated diode laser light from a
diode laser having a central wavelength of 405 nm. The sample was placed above each
of the approximately 3 cm diameter expanded beams at a distance of 25 cm from the
respective Strachan Devices.
[0191] The 674 nm laser diode beam had a peak power of 4.80 mW without optics with about
a 50 percent reduction of power to 2.4 mW after passing through a Thorlabs 5x beam
expander and the Strachan Device. Using the Strachan Device, the 674 nm beam was adjusted
to the 80 percent phase cancellation level to achieve a power of approximately 0.48
mW over a 3 cm diameter expanded beam. The 405 nm beam had a peak power of 11 mW without
optics with about a 50 percent reduction of power to 5.5 mW after passing through
a Thorlabs 5x beam expander and the Strachan Device. The output of the 405 nm beam
was optically phase cancelled using the Strachan Device to achieve a measured 80 percent
reduction of transmitted power to approximately 1.1 mW over a 3 cm diameter expanded
beam. The 674 nm beam was electronically amplitude modulated at 6.25 Megahertz (MHz)
and the 405 nm beam was modulated at 10.8 MHz.
[0192] The solution of atorvastatin calcium and aspirin was treated in the covered Petri
dish for 2.5 minutes with the 674 nm configuration, then for 2.5 minutes with the
405 nm configuration rotating the sample slowly through each respective beam projected
from below the sample. The lid was then removed from the sample and solidification
proceeded by slow evaporation at a room temperature of about 20°C.
[0193] The solvent of the sample evaporated, providing a transparent glass appearance throughout
the entire sample. Figure 69 illustrates the PXRD pattern of the combination of atorvastatin
calcium and aspirin in a 1:1 weight ratio to be highly non-crystalline. Figure 70
illustrates the FTIR spectrum of this sample in which the characteristic peaks of
the individual compounds are present with broadening of the bands that is typical
for non-crystalline forms of compounds.
Comparative Example: Atorvastatin Calcium/Aspirin
[0194] The protocol of Example 15 was repeated comparative with the exception that there
was no application of laser radiation. The resulting material was visibly crystalline,
which was confirmed by PXRD analysis, which demonstrated that a substantial amount
of crystalline material was present. A PXRD pattern for the atorvastatin calcium/aspirin
obtained without the application of the laser radiation is illustrated in Figure 71.
An FTIR analysis of the resulting atorvastatin calcium/aspirin was also performed,
confirming the material was a combination of atorvastatin calcium and aspirin. The
results demonstrate that the non-crystalline atorvastatin calcium/aspirin is not an
artifact of the experiment, but, instead, is a direct result of the application of
the laser radiation in the process of the invention.
[0195] The molecular weight of atorvastatin calcium is 1155.36 and that of aspirin 180.16.
Although the compounds in this combination are in a 1:1 ratio by weight, the smaller
relative size of aspirin results in a molar ratio of aspirin to atorvastatin calcium
of 6.413:1.
Example 16: Preparation of Atorvastatin Free Acid/Aspirin
[0196] The highly non-crystalline glass state of the combination of atorvastatin free acid
and aspirin was produced by applying a sequence of short wavelength followed by long
wavelength laser light modulated and structured by a Strachan Device. A 60 mg sample
of crystalline atorvastatin free acid and a 120 mg sample of crystalline aspirin were
dissolved in 1800 mg of absolute ethanol by stirring at 9000 rpm with a magnetic stirrer,
while heating to 140°C for 10 minutes in a stoppered Erlenmeyer flask. The solution
was filtered, and then divided equally into 6 polystyrene Petri dishes for producing
treated and untreated control samples. Each sample was covered with a polystyrene
lid. The samples were allowed to cool to room temperature.
[0197] The exemplary sample of atorvastatin free acid/aspirin in a weight ratio of 1:2 was
treated with a sequence of laser radiation modified with a Strachan Device. The first
application of amplitude modulated diode laser light was from a diode laser having
a central wavelength of 405 nm. The second application of amplitude modulated diode
laser light from a diode laser having a central wavelength of 674 nm. The sample was
placed above an approximately 3 cm expanded beam at a distance of 25 cm from the Strachan
Device.
[0198] The 405 nm beam had a peak power of 11 mW without optics with about a 50 percent
reduction of power to 5.5 mW after passing through a Thorlabs 5x beam expander and
the Strachan Device. The output of the 405 nm beam was optically phase cancelled using
the Strachan Device to achieve a measured 90 percent reduction of transmitted power
to approximately 0.55 mW over a 3 cm diameter expanded beam. The 674 nm laser diode
beam had a peak power of 4.80 mW without optics with about a 50 percent reduction
of power to 2.4 mW after passing through a Thorlabs 5x beam expander and the Strachan
Device. Using the Strachan Device, the 674 nm beam was adjusted to the 80 percent
phase cancellation level to achieve a power of approximately 0.48 mW over a 3 cm diameter
expanded beam. The 405 nm beam was electronically amplitude modulated at 10.8 MHz,
and the 674 nm beam was modulated at 46.2 MHz.
[0199] The solution of atorvastatin free acid and aspirin was treated in the covered Petri
dish for 2.5 minutes with the 405 nm laser radiation modulated by the Strachan Device,
then for 2.5 minutes with the 674 nm configuration with the samples stationary as
the 3 cm beam covered the entire sample dish. The lid was then removed from the sample
and solidification proceeded by slow evaporation at a room temperature of about 22°C.
[0200] The solvent evaporated, providing a sample having a transparent glass appearance
throughout the entire sample. Figure 72 illustrates the PXRD pattern of the 1:2 weight
ratio combination of atorvastatin free acid and aspirin to be highly non-crystalline.
An FTIR analysis of this sample demonstrated that the characteristic peaks of the
individual compounds are present with broadening of the bands that is typical for
non-crystalline forms of compounds.
Comparative Example: Atorvastatin Free Acid/Aspirin
[0201] The protocol of Example 16 was repeated comparative with the exception that there
was no application of laser radiation. The resulting material was visibly crystalline,
which was confirmed by PXRD analysis, which demonstrated that a substantial amount
of crystalline material was present. A PXRD pattern for the atorvastatin free acid/aspirin
obtained without the application of the laser radiation is illustrated in Figure 73.
An FTIR analysis of the resulting atorvastatin free acid/aspirin was also performed,
confirming the material was a combination of atorvastatin free acid and aspirin. The
results demonstrate that the non-crystalline atorvastatin free acid/aspirin combination
is not an artifact of the experiment, but, instead, is a direct result of the application
of the laser radiation in the process of the invention.
[0202] The molecular weight of atorvastatin free acid is 558.64. Although the compounds
in this combination are in a 1:2 ratio by weight, the smaller relative size of aspirin
results in a molar ratio of aspirin to atorvastatin free acid of 6.202:1.
Example 17: Preparation of Rosuvastatin Calcium/Aspirin
[0203] The highly non-crystalline glass state of the combination of rosuvastatin calcium
and aspirin was produced by applying a repeated sequence of short wavelength followed
by long wavelength laser light modulated and structured by a Strachan Device. A 60
mg sample of rosuvastatin calcium and a 60 mg sample of crystalline aspirin were dissolved
in 1200 mg of absolute ethanol by stirring at 9000 rpm with a magnetic stirrer, while
heating to 140°C for 10 minutes in a stoppered Erlenmeyer flask. The solution was
filtered, and then divided equally into 6 polystyrene Petri dishes for producing treated
and untreated control samples and each sample was covered with a polystyrene lid.
The samples were allowed to cool to room temperature.
[0204] The exemplary sample of rosuvastatin/aspirin in a 1:1 ratio by weight was treated
with a repeated sequence of laser radiation modified with a Strachan Device. The first
application of amplitude modulated diode laser light was from a diode laser having
a central wavelength of 405 nm. The second application of amplitude modulated diode
laser light from a diode laser having a central wavelength of 674 nm. The sample was
placed above an approximately 3 cm expanded beam at a distance of 25 cm from the Strachan
Device.
[0205] The 405 nm beam had a peak power of 11 mW without optics with about a 50 percent
reduction of power to 5.5 mW after passing through a Thorlabs 5x beam expander and
the Strachan Device. The output of the 405 nm beam was optically phase cancelled using
the Strachan Device to achieve a measured 90 percent reduction of transmitted power
to approximately 0.55 mW over a 3 cm diameter expanded beam. The 674 nm laser diode
beam had a peak power of 4.80 mW without optics with about a 50 percent reduction
of power to 2.4 mW after passing through a Thorlabs 5x beam expander and the Strachan
Device. Using the Strachan Device, the 674 nm beam was adjusted to the 80 percent
phase cancellation level to achieve a power of approximately 0.48 mW over a 3 cm diameter
expanded beam. The 405 nm beam was electronically amplitude modulated at 10.8 MHz
and the 674 nm beam was modulated at 46.2 MHz.
[0206] The solution of rosuvastatin calcium and aspirin was treated in the covered Petri
dish for 1 minute with the 405 nm configuration, then for 1 minute with the 674 nm
configuration with the samples stationary as each of the 3 cm beams covered the entire
sample dish. This was repeated for two more identical cycles for a total treatment
duration of 6 minutes. The lid was then removed from the sample and solidification
proceeded by slow evaporation at a room temperature of about 23°C.
[0207] The solvent in the sample evaporated, providing a transparent glass appearance throughout
the entire sample. Figure 74 illustrates the PXRD pattern of the 1:1 weight ratio
combination of rosuvastatin calcium and aspirin to be highly non-crystalline. An FTIR
analysis of this sample demonstrates that the characteristic peaks of the individual
compounds are present with broadening of the bands that is typical for non-crystalline
forms of compounds.
Comparative Example: Rosuvastatin Calcium/Aspirin
[0208] The protocol of Example 17 was repeated comparative with the exception that there
was no application of laser radiation. The resulting material was visibly crystalline,
which was confirmed by PXRD analysis, which demonstrated that a substantial amount
of crystalline material was present. A PXRD pattern for the rosuvastatin calcium/aspirin
obtained without the application of the laser radiation is illustrated in Figure 75.
An FTIR analysis of the resulting rosuvastatin calcium/aspirin was also performed,
confirming the material was a combination of rosuvastatin calcium and aspirin. The
results demonstrate that the non-crystalline combination of rosuvastatin calcium and
aspirin is not an artifact of the experiment, but, instead, is a direct result of
the application of the laser radiation in the process of the invention.
[0209] The molecular weight of rosuvastatin calcium is 1001.14. Although the compounds in
this combination are in a 1:1 ratio by weight, the smaller relative size of aspirin
results in a molar ratio of aspirin to atorvastatin free acid of 5.557:1.
Example 18: Preparation of Simvastatin/Aspirin
[0210] The highly non-crystalline glass state of the combination of simvastatin and aspirin
was produced by applying a repeated sequence of short wavelength followed by long
wavelength laser light modulated and structured by a Strachan Device. A 60 mg sample
of crystalline simvastatin and a 30 mg sample of crystalline aspirin were dissolved
in 900 mg of absolute ethanol by stirring at 9000 rpm with a magnetic stirrer, while
heating to 140°C for 10 minutes in a stoppered Erlenmeyer flask. The solution was
filtered, and then divided equally into 6 polystyrene Petri dishes for producing treated
and untreated control samples. Each sample was covered with a polystyrene lid. The
samples were allowed to cool to room temperature.
[0211] The exemplary sample of simvastatin/aspirin in a 2:1 ratio by weight was treated
with a repeated sequence of laser radiation modified with a Strachan Device. The first
application of amplitude modulated diode laser light was from a diode laser having
a central wavelength of 405 nm. The second application of amplitude modulated diode
laser light from a diode laser having a central wavelength of 674 nm. The sample was
placed above each of the approximately 3 cm expanded beams at a distance of 25 cm
from the Strachan Device.
[0212] The 405 nm beam had a peak power of 11 mW without optics with about a 50 percent
reduction of power to 5.5 mW after passing through a Thorlabs 5x beam expander and
the Strachan Device. The output of the 405 nm beam was optically phase cancelled using
the Strachan Device to achieve a measured 90 percent reduction of transmitted power
to approximately 0.55 mW over a 3 cm diameter expanded beam. The 674 nm laser diode
beam had a peak power of 4.80 mW without optics with about a 50 percent reduction
of power to 2.4 mW after passing through a Thorlabs 5x beam expander and the Strachan
Device. Using the Strachan Device, the 674 nm beam was adjusted to the 80 percent
phase cancellation level to achieve a power of approximately 0.48 mW over a 3 cm diameter
expanded beam. The 405 nm beam was electronically amplitude modulated at 10.8 MHz
and the 674 nm beam was modulated at 46.2 MHz.
[0213] The solution of simvastatin and aspirin was treated in the covered Petri dish for
1 minute with the 405 nm configuration, then for 1 minute with the 674 nm configuration
with the samples stationary as each of the 3 cm diameter beams covered the entire
sample dish. This was repeated for two more identical cycles for a total treatment
duration of 6 minutes. The lid was then removed from the sample and solidification
proceeded by slow evaporation at a room temperature of 21°C.
[0214] The solvent in the sample evaporated, providing a transparent glass appearance throughout
the entire sample. Figure 76 illustrates the PXRD pattern of the 2:1 weight ratio
combination of simvastatin and aspirin to be highly non-crystalline. Figure 77 illustrates
the FTIR analysis of this sample to indicate that the characteristic peaks of the
individual compounds are present with broadening of the bands that is typical for
non-crystalline forms of compounds.
Comparative Example: Simvastatin/Aspirin
[0215] The protocol of Example 18 was repeated comparative with the exception that there
was no application of laser radiation. The resulting material was visibly crystalline,
which was confirmed by PXRD analysis, which demonstrated that a substantial amount
of crystalline material was present. A PXRD pattern for the simvastatin/aspirin obtained
without the application of the laser radiation is illustrated in Figure 78. An FTIR
analysis of the resulting simvastatin/aspirin was also performed, confirming the material
was a combination of simvastatin and aspirin. The results demonstrate that the non-crystalline
simvastatin/aspirin is not an artifact of the experiment, but, instead, is a direct
result of the application of the laser radiation in the process of the invention.
[0216] The molecular weight of simvastatin is 418.56. Although the compounds in this combination
are in a 1:1 ratio by weight, the smaller relative size of aspirin results in a molar
ratio of aspirin to atorvastatin free acid of 1.162:1.
[0217] The ability to stabilize a room temperature glass form of aspirin into which single
molecules or small clusters of molecules are embedded offers marked enhancement of
solubility for the embedded compounds. To the degree a compound is hydrophobic and
of low aqueous solubility, surrounding this compound in a matrix of glass aspirin
of much higher solubility, the rate of dissolution, bioavailability, and absorption
of the hydrophobic compound or compounds will be enhanced. The greater the relative
molar ratio of aspirin and the higher the intrinsic solubility of the embedded compound,
the greater the likely solubility of the co-amorphous combination.
[0218] As an example, the solubility of crystalline simvastatin in water is 0.03 mg/ml,
which is relatively low. In contrast, the solubility of crystalline aspirin in water
is 3.33 mg/ml at room temperature, a 111-fold differential. By producing both simvastatin
and aspirin in an amorphous state, which often increases the solubility of hydrophobic
compounds by a factor of 2- to 8-fold and embedding the simvastatin with a matrix
of non-crystalline aspirin, it is expected that the solubility of simvastatin will
be significantly increased.
[0219] For the particularly high molar ratios achieved with the co-amorphous combination
of aspirin with atorvastatin calcium, atorvastatin free acid, and rosuvastatin calcium,
aspirin molecules can completely surround individual or a few molecules of the embedded
statin. In this manner pockets are formed within the non-crystalline matrix of aspirin
at the scale of nanometers, and this system could be described as a glass aspirin
nanopocket packaging and delivery system for relatively less soluble compounds. The
combination of aspirin (or other suitable matrix compound that could be prepared through
this method) with a statin can create an environment that confers greater long-term
stability of the non-crystalline state of the statin or other hydrophobic or poorly
soluble compound or compounds thus embedded.
[0220] The pharmacological benefit of the statins is primarily focused on reducing total
and LDL cholesterol. Use of statins has been associated with the observation of the
reduction of systemic inflammatory markers such as C-reactive protein. Reduced total
and especially LDL cholesterol levels as well as decreased systemic inflammation have
been identified as factors that improve cardiovascular health outcomes. Aspirin has
well demonstrated effects on reducing the tendency to vascular clot formation that
is independently associated with improved cardiovascular outcomes. The particular
pairing of a statin and aspirin together in a co-absorbed matrix will offer additive
and even synergistic benefits for cardiac and vascular health.
[0221] Particularly pronounced therapeutic enhancement is anticipated for atorvastatin.
With absorption of only 30 percent, solubility enhancement may promote considerably
greater initial absorption. To the degree that absorption is enhanced, the current
systemic bioavailability of 12 percent may be commensurately increased. The ability
to achieve comparable or greater clinical benefits at lower doses can reduce the side
effect profile and make statins acceptable to a wider number of persons who may benefit
from the pharmacology of statins.
[0222] To achieve large scale production of this form, microencapsulation permits generation
and sealing of smaller particle sizes that are intrinsically more stable than larger
particles composed of the non-crystalline aspirin and statins or other compounds in
a co-amorphous combination. Microencapsulation will facilitate retaining stability
during long term storage over a wider range of temperature and humidity. Microencapsulation
techniques are well known in the art.
[0223] Whereas ezetimibe and the statins described in this disclosure were readily produced
in the non-crystalline state as individual compounds and as co-amorphous glass combinations
of ezetimibe and a statin, when aspirin was added to this combination there was a
concentration threshold above which a tendency to crystallization occurred. When ezetimibe
and a statin were combined in an equal ratio by weight and aspirin was added to produce
a 1:1:1 ratio of ezetimibe/statin/aspirin, fine threads of crystals appeared in an
otherwise transparent glass matrix, most likely reflecting aggregation of crystallizing
aspirin. When aspirin was reduced in proportion to the 2:2:1 weight ratio for the
ezetimibe/statin/aspirin composition, a stable co-amorphous glass form was readily
produced with the process of the invention. Thus, it appears that this method can
produce stable co-amorphous combinations of ezetimibe and a statin in a wide range
of ratios and aspirin can be added to the combination at a level of up to at least
about 20 percent by weight to produce a stable highly co-amorphous combination of
ezetimibe, a statin, and plus aspirin.
[0224] The molecular structures of the compounds treated in the examples of the invention
describe above are significantly different, as shown below.
Aspirin,
Simvastatin,
Ezetimibe,
Atorvastatin free acid,
Atorvastatin calcium,
and
Rosuvastatin calcium,
[0225] As the molecular structures for those compounds differ significantly, those skilled
in the art would expect the molecular orbitals and spectroscopic absorption bands
of each of those compounds to also be significantly different, such that different
laser wavelengths were required to effect the observed changes. However, as disclosed
above, non-crystalline and co-amorphous compositions of those compounds were prepared
by treatment with the process of the invention. For each composition in each example,
the laser radiation from diode lasers emitting at essentially the same two wavelengths
was modified by transmission through a Strachan Device, and applied to the composition.
That is, there was no significant difference in the emission spectra of the lasers
used in each example. One of the diode lasers used in the examples emitted laser radiation
in the violet range having a wavelength centered at about 408 nm (Examples 1 to 14)
or at about 405 nm (Examples 15 to 18). The other diode laser used in the examples
emitted laser radiation having a wavelength centered at about 674 nm. Each example
provided a non-crystalline form of the composition, despite the differences in molecular
structure.
[0226] As discussed above, without being bound by theory, it is believed that the output
bandwidth of the lasers is broadened by the short pulse length. This follows from
the Uncertainty Principle. As a result, the short pulses of laser light are believed
to provide photons that interact with the different vibrational and/or electronic
states of the compositions to provide the non-crystalline forms. Lasers having an
emission that corresponds to specific absorption bands of the compositions are not
required. Accordingly, it is submitted that the process of the invention can be readily
extended to other pharmaceutical and organic compositions.